KMT2D: Difference between revisions

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'''Histone-lysine N-methyltransferase 2D''' (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase.<ref name="elife">{{cite journal | vauthors = Lee JE, Wang C, Xu S, Cho YW, Wang L, Feng X, Baldridge A, Sartorelli V, Zhuang L, Peng W, Ge K | display-authors = 6 | title = H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation | journal = eLife | volume = 2 | pages = e01503 | date = December 2013 | pmid = 24368734 | doi = 10.7554/eLife.01503 }}</ref> It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A (or MLL1), KMT2B (or MLL2), KMT2C (or MLL3), KMT2F (or SET1A), and KMT2G (or SET1B).  KMT2D is a large protein over 5,500 amino acids in size and is widely expressed in adult tissues.<ref name="prasad">{{cite journal | vauthors = Prasad R, Zhadanov AB, Sedkov Y, Bullrich F, Druck T, Rallapalli R, Yano T, Alder H, Croce CM, Huebner K, Mazo A, Canaani E | display-authors = 6 | title = Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax | journal = Oncogene | volume = 15 | issue = 5 | pages = 549–60 | date = July 1997 | pmid = 9247308 | doi = 10.1038/sj.onc.1201211 }}</ref> The protein co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development.<ref name="elife" /> It also plays critical roles in regulating cell fate transition,<ref name="elife" /><ref name="Wang 2016 enhancer priming">{{cite journal | vauthors = Wang C, Lee JE, Lai B, Macfarlan TS, Xu S, Zhuang L, Liu C, Peng W, Ge K | title = Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 42 | pages = 11871–11876 | date = October 2016 | pmid = 27698142 | doi = 10.1073/pnas.1606857113 }}</ref><ref name="dhar trans-tail">{{cite journal | vauthors = Dhar SS, Lee SH, Kan PY, Voigt P, Ma L, Shi X, Reinberg D, Lee MG | title = Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4 | journal = Genes & Development | volume = 26 | issue = 24 | pages = 2749–62 | date = December 2012 | pmid = 23249737 | doi = 10.1101/gad.203356.112 }}</ref><ref name="munehira">{{cite journal | vauthors = Munehira Y, Yang Z, Gozani O | title = Systematic Analysis of Known and Candidate Lysine Demethylases in the Regulation of Myoblast Differentiation | journal = Journal of Molecular Biology | date = October 2016 | pmid = 27732873 | doi = 10.1016/j.jmb.2016.10.004 }}</ref> metabolism,<ref name="kim 2015">{{cite journal | vauthors = Kim DH, Rhee JC, Yeo S, Shen R, Lee SK, Lee JW, Lee S | title = Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice | journal = Hepatology | volume = 61 | issue = 3 | pages = 1012–23 | date = March 2015 | pmid = 25346535 | doi = 10.1002/hep.27578 }}</ref><ref name="kim 2016">{{cite journal | vauthors = Kim DH, Kim J, Kwon JS, Sandhu J, Tontonoz P, Lee SK, Lee S, Lee JW | title = Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2 | journal = Cell Reports | volume = 17 | issue = 6 | pages = 1671–1682 | date = November 2016 | pmid = 27806304 | doi = 10.1016/j.celrep.2016.10.023 }}</ref> and tumor suppression.<ref name="zhang 2015 B cell">{{cite journal | vauthors = Zhang J, Dominguez-Sola D, Hussein S, Lee JE, Holmes AB, Bansal M, Vlasevska S, Mo T, Tang H, Basso K, Ge K, Dalla-Favera R, Pasqualucci L | display-authors = 6 | title = Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis | journal = Nature Medicine | volume = 21 | issue = 10 | pages = 1190–8 | date = October 2015 | pmid = 26366712 | doi = 10.1038/nm.3940 }}</ref><ref name="lee 2009 p53">{{cite journal | vauthors = Lee J, Kim DH, Lee S, Yang QH, Lee DK, Lee SK, Roeder RG, Lee JW | title = A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 21 | pages = 8513–8 | date = May 2009 | pmid = 19433796 | doi = 10.1073/pnas.0902873106 }}</ref><ref name="chen 2014 mll3 tumor suppressor">{{cite journal | vauthors = Chen C, Liu Y, Rappaport AR, Kitzing T, Schultz N, Zhao Z, Shroff AS, Dickins RA, Vakoc CR, Bradner JE, Stock W, LeBeau MM, Shannon KM, Kogan S, Zuber J, Lowe SW | title = MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia | journal = Cancer Cell | volume = 25 | issue = 5 | pages = 652–65 | date = May 2014 | pmid = 24794707 | doi = 10.1016/j.ccr.2014.03.016 }}</ref><ref name="ortega-molina">{{cite journal | vauthors = Ortega-Molina A, Boss IW, Canela A, Pan H, Jiang Y, Zhao C, Jiang M, Hu D, Agirre X, Niesvizky I, Lee JE, Chen HT, Ennishi D, Scott DW, Mottok A, Hother C, Liu S, Cao XJ, Tam W, Shaknovich R, Garcia BA, Gascoyne RD, Ge K, Shilatifard A, Elemento O, Nussenzweig A, Melnick AM, Wendel HG | display-authors = 6 | title = The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development | journal = Nature Medicine | volume = 21 | issue = 10 | pages = 1199–208 | date = October 2015 | pmid = 26366710 | doi = 10.1038/nm.3943 }}</ref> Mutations in KMT2D have been associated with Kabuki Syndrome,<ref name="Ng kabuki">{{cite journal | vauthors = Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J | display-authors = 6 | title = Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome | journal = Nature Genetics | volume = 42 | issue = 9 | pages = 790–3 | date = September 2010 | pmid = 20711175 | doi = 10.1038/ng.646 }}</ref> congenital heart disease,<ref name="zaidi CHD">{{cite journal | vauthors = Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, Romano-Adesman A, Bjornson RD, Breitbart RE, Brown KK, Carriero NJ, Cheung YH, Deanfield J, DePalma S, Fakhro KA, Glessner J, Hakonarson H, Italia MJ, Kaltman JR, Kaski J, Kim R, Kline JK, Lee T, Leipzig J, Lopez A, Mane SM, Mitchell LE, Newburger JW, Parfenov M, Pe'er I, Porter G, Roberts AE, Sachidanandam R, Sanders SJ, Seiden HS, State MW, Subramanian S, Tikhonova IR, Wang W, Warburton D, White PS, Williams IA, Zhao H, Seidman JG, Brueckner M, Chung WK, Gelb BD, Goldmuntz E, Seidman CE, Lifton RP | display-authors = 6 | title = De novo mutations in histone-modifying genes in congenital heart disease | journal = Nature | volume = 498 | issue = 7453 | pages = 220–3 | date = June 2013 | pmid = 23665959 | doi = 10.1038/nature12141 }}</ref> and various forms of cancer.<ref name="rao KMT2 review">{{cite journal | vauthors = Rao RC, Dou Y | title = Hijacked in cancer: the KMT2 (MLL) family of methyltransferases | journal = Nature Reviews. Cancer | volume = 15 | issue = 6 | pages = 334–46 | date = June 2015 | pmid = 25998713 | doi = 10.1038/nrc3929 }}</ref>
'''Histone-lysine N-methyltransferase 2D''' (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase.<ref name="elife">{{cite journal | vauthors = Lee JE, Wang C, Xu S, Cho YW, Wang L, Feng X, Baldridge A, Sartorelli V, Zhuang L, Peng W, Ge K | display-authors = 6 | title = H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation | journal = eLife | volume = 2 | pages = e01503 | date = December 2013 | pmid = 24368734 | doi = 10.7554/eLife.01503 | pmc=3869375}}</ref> It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A (or MLL1), KMT2B (or MLL2), KMT2C (or MLL3), KMT2F (or SET1A), and KMT2G (or SET1B).  KMT2D is a large protein over 5,500 amino acids in size and is widely expressed in adult tissues.<ref name="prasad">{{cite journal | vauthors = Prasad R, Zhadanov AB, Sedkov Y, Bullrich F, Druck T, Rallapalli R, Yano T, Alder H, Croce CM, Huebner K, Mazo A, Canaani E | display-authors = 6 | title = Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax | journal = Oncogene | volume = 15 | issue = 5 | pages = 549–60 | date = July 1997 | pmid = 9247308 | doi = 10.1038/sj.onc.1201211 }}</ref> The protein co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development.<ref name="elife" /> It also plays critical roles in regulating cell fate transition,<ref name="elife" /><ref name="Wang 2016 enhancer priming">{{cite journal | vauthors = Wang C, Lee JE, Lai B, Macfarlan TS, Xu S, Zhuang L, Liu C, Peng W, Ge K | title = Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 42 | pages = 11871–11876 | date = October 2016 | pmid = 27698142 | doi = 10.1073/pnas.1606857113 | pmc=5081576}}</ref><ref name="dhar trans-tail">{{cite journal | vauthors = Dhar SS, Lee SH, Kan PY, Voigt P, Ma L, Shi X, Reinberg D, Lee MG | title = Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4 | journal = Genes & Development | volume = 26 | issue = 24 | pages = 2749–62 | date = December 2012 | pmid = 23249737 | doi = 10.1101/gad.203356.112 | pmc=3533079}}</ref><ref name="munehira">{{cite journal | vauthors = Munehira Y, Yang Z, Gozani O | title = Systematic Analysis of Known and Candidate Lysine Demethylases in the Regulation of Myoblast Differentiation | journal = Journal of Molecular Biology | date = October 2016 | pmid = 27732873 | doi = 10.1016/j.jmb.2016.10.004 | volume=429 | pmc=5388604 | pages=2055–2065}}</ref> metabolism,<ref name="kim 2015">{{cite journal | vauthors = Kim DH, Rhee JC, Yeo S, Shen R, Lee SK, Lee JW, Lee S | title = Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice | journal = Hepatology | volume = 61 | issue = 3 | pages = 1012–23 | date = March 2015 | pmid = 25346535 | doi = 10.1002/hep.27578 | pmc=4474368}}</ref><ref name="kim 2016">{{cite journal | vauthors = Kim DH, Kim J, Kwon JS, Sandhu J, Tontonoz P, Lee SK, Lee S, Lee JW | title = Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2 | journal = Cell Reports | volume = 17 | issue = 6 | pages = 1671–1682 | date = November 2016 | pmid = 27806304 | doi = 10.1016/j.celrep.2016.10.023 }}</ref> and tumor suppression.<ref name="zhang 2015 B cell">{{cite journal | vauthors = Zhang J, Dominguez-Sola D, Hussein S, Lee JE, Holmes AB, Bansal M, Vlasevska S, Mo T, Tang H, Basso K, Ge K, Dalla-Favera R, Pasqualucci L | display-authors = 6 | title = Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis | journal = Nature Medicine | volume = 21 | issue = 10 | pages = 1190–8 | date = October 2015 | pmid = 26366712 | doi = 10.1038/nm.3940 | pmc=5145002}}</ref><ref name="lee 2009 p53">{{cite journal | vauthors = Lee J, Kim DH, Lee S, Yang QH, Lee DK, Lee SK, Roeder RG, Lee JW | title = A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 21 | pages = 8513–8 | date = May 2009 | pmid = 19433796 | doi = 10.1073/pnas.0902873106 | pmc=2689008}}</ref><ref name="chen 2014 mll3 tumor suppressor">{{cite journal | vauthors = Chen C, Liu Y, Rappaport AR, Kitzing T, Schultz N, Zhao Z, Shroff AS, Dickins RA, Vakoc CR, Bradner JE, Stock W, LeBeau MM, Shannon KM, Kogan S, Zuber J, Lowe SW | title = MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia | journal = Cancer Cell | volume = 25 | issue = 5 | pages = 652–65 | date = May 2014 | pmid = 24794707 | doi = 10.1016/j.ccr.2014.03.016 | pmc=4206212}}</ref><ref name="ortega-molina">{{cite journal | vauthors = Ortega-Molina A, Boss IW, Canela A, Pan H, Jiang Y, Zhao C, Jiang M, Hu D, Agirre X, Niesvizky I, Lee JE, Chen HT, Ennishi D, Scott DW, Mottok A, Hother C, Liu S, Cao XJ, Tam W, Shaknovich R, Garcia BA, Gascoyne RD, Ge K, Shilatifard A, Elemento O, Nussenzweig A, Melnick AM, Wendel HG | display-authors = 6 | title = The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development | journal = Nature Medicine | volume = 21 | issue = 10 | pages = 1199–208 | date = October 2015 | pmid = 26366710 | doi = 10.1038/nm.3943 | pmc=4676270}}</ref> Mutations in KMT2D have been associated with Kabuki Syndrome,<ref name="Ng kabuki">{{cite journal | vauthors = Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J | display-authors = 6 | title = Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome | journal = Nature Genetics | volume = 42 | issue = 9 | pages = 790–3 | date = September 2010 | pmid = 20711175 | doi = 10.1038/ng.646 | pmc=2930028}}</ref> congenital heart disease,<ref name="zaidi CHD">{{cite journal | vauthors = Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, Romano-Adesman A, Bjornson RD, Breitbart RE, Brown KK, Carriero NJ, Cheung YH, Deanfield J, DePalma S, Fakhro KA, Glessner J, Hakonarson H, Italia MJ, Kaltman JR, Kaski J, Kim R, Kline JK, Lee T, Leipzig J, Lopez A, Mane SM, Mitchell LE, Newburger JW, Parfenov M, Pe'er I, Porter G, Roberts AE, Sachidanandam R, Sanders SJ, Seiden HS, State MW, Subramanian S, Tikhonova IR, Wang W, Warburton D, White PS, Williams IA, Zhao H, Seidman JG, Brueckner M, Chung WK, Gelb BD, Goldmuntz E, Seidman CE, Lifton RP | display-authors = 6 | title = De novo mutations in histone-modifying genes in congenital heart disease | journal = Nature | volume = 498 | issue = 7453 | pages = 220–3 | date = June 2013 | pmid = 23665959 | doi = 10.1038/nature12141 | pmc=3706629| url = https://dash.harvard.edu/bitstream/handle/1/11879354/3706629.pdf?sequence=1 }}</ref> and various forms of cancer.<ref name="rao KMT2 review">{{cite journal | vauthors = Rao RC, Dou Y | title = Hijacked in cancer: the KMT2 (MLL) family of methyltransferases | journal = Nature Reviews. Cancer | volume = 15 | issue = 6 | pages = 334–46 | date = June 2015 | pmid = 25998713 | doi = 10.1038/nrc3929 | pmc=4493861}}</ref>


== Structure ==
== Structure ==
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=== Protein ===
=== Protein ===
KMT2D is homologous to Trithorax-related (Trr), which is a [[Trithorax-group protein]].<ref name="mohan">{{cite journal | vauthors = Mohan M, Herz HM, Smith ER, Zhang Y, Jackson J, Washburn MP, Florens L, Eissenberg JC, Shilatifard A | title = The COMPASS family of H3K4 methylases in Drosophila | journal = Molecular and Cellular Biology | volume = 31 | issue = 21 | pages = 4310–8 | date = November 2011 | pmid = 21875999 | doi = 10.1128/MCB.06092-11 }}</ref> The mouse and human KMT2D proteins are 5,588 and 5,537 amino acids in length, respectively. Both species of the protein weigh about 600 kDa.<ref name="Mouse ensemble" /><ref name="human ensemble" /> KMT2D contains an enzymatically active C-terminal SET domain that is responsible for its methyltransferase activity and maintaining protein stability in cells.<ref name="ruthenburg review">{{cite journal | vauthors = Ruthenburg AJ, Allis CD, Wysocka J | title = Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark | journal = Molecular Cell | volume = 25 | issue = 1 | pages = 15–30 | date = January 2007 | pmid = 17218268 | doi = 10.1016/j.molcel.2006.12.014 }}</ref> Near the SET domain are a plant homeotic domain (PHD) and FY-rich N/C-terminal (FYRN and FYRC) domains. The protein also contains six N-terminal PHDs, a high mobility group (HMG-I), and nine nuclear receptor interacting motifs (LXXLLs).<ref name="rao KMT2 review" /> It was shown that amino acids Y5426 and Y5512 are critical for the enzymatic activity of human KMT2D ''in vitro''.<ref name="jang YH">{{cite journal | vauthors = Jang Y, Wang C, Zhuang L, Liu C, Ge K | title = H3K4 Methyltransferase Activity Is Required for MLL4 Protein Stability | journal = Journal of Molecular Biology | date = December 2016 | pmid = 28013028 | doi = 10.1016/j.jmb.2016.12.016 }}</ref> In addition, mutation of Y5477 in mouse KMT2D, which corresponds to Y5426 in human KMT2D, resulted in the inactivation of KMT2D's enzymatic activity in embryonic stem cells.<ref>{{cite journal | vauthors = Dorighi KM, Swigut T, Henriques T, Bhanu NV, Scruggs BS, Nady N, Still CD, Garcia BA, Adelman K, Wysocka J | title = Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation | journal = Molecular Cell | date = May 2017 | pmid = 28483418 | doi = 10.1016/j.molcel.2017.04.018 }}</ref> Depletion of cellular H3K4 methylation reduces KMT2D levels, indicating that the protein's stability could be regulated by cellular H3K4 methylation.<ref name="jang YH" />
KMT2D is homologous to Trithorax-related (Trr), which is a [[Trithorax-group protein]].<ref name="mohan">{{cite journal | vauthors = Mohan M, Herz HM, Smith ER, Zhang Y, Jackson J, Washburn MP, Florens L, Eissenberg JC, Shilatifard A | title = The COMPASS family of H3K4 methylases in Drosophila | journal = Molecular and Cellular Biology | volume = 31 | issue = 21 | pages = 4310–8 | date = November 2011 | pmid = 21875999 | doi = 10.1128/MCB.06092-11 | pmc=3209330}}</ref> The mouse and human KMT2D proteins are 5,588 and 5,537 amino acids in length, respectively. Both species of the protein weigh about 600 kDa.<ref name="Mouse ensemble" /><ref name="human ensemble" /> KMT2D contains an enzymatically active C-terminal SET domain that is responsible for its methyltransferase activity and maintaining protein stability in cells.<ref name="ruthenburg review">{{cite journal | vauthors = Ruthenburg AJ, Allis CD, Wysocka J | title = Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark | journal = Molecular Cell | volume = 25 | issue = 1 | pages = 15–30 | date = January 2007 | pmid = 17218268 | doi = 10.1016/j.molcel.2006.12.014 }}</ref> Near the SET domain are a plant homeotic domain (PHD) and FY-rich N/C-terminal (FYRN and FYRC) domains. The protein also contains six N-terminal PHDs, a high mobility group (HMG-I), and nine nuclear receptor interacting motifs (LXXLLs).<ref name="rao KMT2 review" /> It was shown that amino acids Y5426 and Y5512 are critical for the enzymatic activity of human KMT2D ''in vitro''.<ref name="jang YH">{{cite journal | vauthors = Jang Y, Wang C, Zhuang L, Liu C, Ge K | title = H3K4 Methyltransferase Activity Is Required for MLL4 Protein Stability | journal = Journal of Molecular Biology | date = December 2016 | pmid = 28013028 | doi = 10.1016/j.jmb.2016.12.016 | volume=429 | pmc=5474351 | pages=2046–2054}}</ref> In addition, mutation of Y5477 in mouse KMT2D, which corresponds to Y5426 in human KMT2D, resulted in the inactivation of KMT2D's enzymatic activity in embryonic stem cells.<ref>{{cite journal | vauthors = Dorighi KM, Swigut T, Henriques T, Bhanu NV, Scruggs BS, Nady N, Still CD, Garcia BA, Adelman K, Wysocka J | title = Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation | journal = Molecular Cell | date = May 2017 | pmid = 28483418 | doi = 10.1016/j.molcel.2017.04.018 | volume=66 | pmc=5662137 | pages=568–576.e4}}</ref> Depletion of cellular H3K4 methylation reduces KMT2D levels, indicating that the protein's stability could be regulated by cellular H3K4 methylation.<ref name="jang YH" />


=== Protein complex ===
=== Protein complex ===
Several components of the KMT2D complex were first purified in 2003,<ref name="goo 2003">{{cite journal | vauthors = Goo YH, Sohn YC, Kim DH, Kim SW, Kang MJ, Jung DJ, Kwak E, Barlev NA, Berger SL, Chow VT, Roeder RG, Azorsa DO, Meltzer PS, Suh PG, Song EJ, Lee KJ, Lee YC, Lee JW | title = Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins | journal = Molecular and Cellular Biology | volume = 23 | issue = 1 | pages = 140–9 | date = January 2003 | pmid = 12482968 }}</ref> and then the entire complex was identified in 2007.<ref name="cho PTIP">{{cite journal | vauthors = Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K | title = PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex | journal = The Journal of Biological Chemistry | volume = 282 | issue = 28 | pages = 20395–406 | date = July 2007 | pmid = 17500065 | doi = 10.1074/jbc.M701574200 }}</ref><ref name="Issaeva 2007">{{cite journal | vauthors = Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce CM, Nakamura T, Mazo A, Eisenbach L, Canaani E | title = Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth | journal = Molecular and Cellular Biology | volume = 27 | issue = 5 | pages = 1889–903 | date = March 2007 | pmid = 17178841 | doi = 10.1128/MCB.01506-06 }}</ref><ref name="Lee 2007">{{cite journal | vauthors = Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Di Croce L, Shiekhattar R | title = Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination | journal = Science | volume = 318 | issue = 5849 | pages = 447–50 | date = October 2007 | pmid = 17761849 | doi = 10.1126/science.1149042 }}</ref><ref name="patel 2008">{{cite journal | vauthors = Patel A, Vought VE, Dharmarajan V, Cosgrove MS | title = A conserved arginine-containing motif crucial for the assembly and enzymatic activity of the mixed lineage leukemia protein-1 core complex | journal = The Journal of Biological Chemistry | volume = 283 | issue = 47 | pages = 32162–75 | date = November 2008 | pmid = 18829457 | doi = 10.1074/jbc.M806317200 }}</ref> Along with KMT2D, the complex also contains ASH2L, RbBP5, WDR5, DPY30, NCOA6, UTX (also known as KDM6A), PA1, and PTIP. WDR5, RbBP5, ASH2L, and DPY30 form the four-subunit sub-complex WRAD, which is critical for H3K4 methyltransferase activity in all mammalian Set1-like histone methyltransferase complexes.<ref>{{cite journal | vauthors = Ernst P, Vakoc CR | title = WRAD: enabler of the SET1-family of H3K4 methyltransferases | journal = Briefings in Functional Genomics | volume = 11 | issue = 3 | pages = 217–26 | date = May 2012 | pmid = 22652693 | doi = 10.1093/bfgp/els017 }}</ref> WDR5 binds directly with FYRN/FYRC domains of C-terminal SET domain-containing fragments of human KMT2C and KMT2D.<ref name="cho PTIP" /> UTX, the complex’s H3K27 demethylase, PTIP, and PA1 are subunits that are unique to KMT2C and KMT2D.<ref name="cho PTIP" /><ref name="cho 2012">{{cite journal | vauthors = Cho YW, Hong S, Ge K | title = Affinity purification of MLL3/MLL4 histone H3K4 methyltransferase complex | journal = Methods in Molecular Biology | volume = 809 | pages = 465–72 | date = 2012 | pmid = 22113294 | doi = 10.1007/978-1-61779-376-9_30 }}</ref><ref name="Hong UTX">{{cite journal | vauthors = Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K | title = Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 47 | pages = 18439–44 | date = November 2007 | pmid = 18003914 | doi = 10.1073/pnas.0707292104 }}</ref> KMT2D acts as a scaffold protein within the complex; absence of KMT2D results in destabilization of UTX and collapse of the complex in cells.<ref name="elife" /><ref name="jang YH" />
Several components of the KMT2D complex were first purified in 2003,<ref name="goo 2003">{{cite journal | vauthors = Goo YH, Sohn YC, Kim DH, Kim SW, Kang MJ, Jung DJ, Kwak E, Barlev NA, Berger SL, Chow VT, Roeder RG, Azorsa DO, Meltzer PS, Suh PG, Song EJ, Lee KJ, Lee YC, Lee JW | title = Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins | journal = Molecular and Cellular Biology | volume = 23 | issue = 1 | pages = 140–9 | date = January 2003 | pmid = 12482968 | doi=10.1128/mcb.23.1.140-149.2003 | pmc=140670}}</ref> and then the entire complex was identified in 2007.<ref name="cho PTIP">{{cite journal | vauthors = Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K | title = PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex | journal = The Journal of Biological Chemistry | volume = 282 | issue = 28 | pages = 20395–406 | date = July 2007 | pmid = 17500065 | doi = 10.1074/jbc.M701574200 | pmc=2729684}}</ref><ref name="Issaeva 2007">{{cite journal | vauthors = Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce CM, Nakamura T, Mazo A, Eisenbach L, Canaani E | title = Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth | journal = Molecular and Cellular Biology | volume = 27 | issue = 5 | pages = 1889–903 | date = March 2007 | pmid = 17178841 | doi = 10.1128/MCB.01506-06 | pmc=1820476}}</ref><ref name="Lee 2007">{{cite journal | vauthors = Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Di Croce L, Shiekhattar R | title = Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination | journal = Science | volume = 318 | issue = 5849 | pages = 447–50 | date = October 2007 | pmid = 17761849 | doi = 10.1126/science.1149042 }}</ref><ref name="patel 2008">{{cite journal | vauthors = Patel A, Vought VE, Dharmarajan V, Cosgrove MS | title = A conserved arginine-containing motif crucial for the assembly and enzymatic activity of the mixed lineage leukemia protein-1 core complex | journal = The Journal of Biological Chemistry | volume = 283 | issue = 47 | pages = 32162–75 | date = November 2008 | pmid = 18829457 | doi = 10.1074/jbc.M806317200 }}</ref> Along with KMT2D, the complex also contains ASH2L, RbBP5, WDR5, DPY30, NCOA6, UTX (also known as KDM6A), PA1, and PTIP. WDR5, RbBP5, ASH2L, and DPY30 form the four-subunit sub-complex WRAD, which is critical for H3K4 methyltransferase activity in all mammalian Set1-like histone methyltransferase complexes.<ref>{{cite journal | vauthors = Ernst P, Vakoc CR | title = WRAD: enabler of the SET1-family of H3K4 methyltransferases | journal = Briefings in Functional Genomics | volume = 11 | issue = 3 | pages = 217–26 | date = May 2012 | pmid = 22652693 | doi = 10.1093/bfgp/els017 | pmc=3388306}}</ref> WDR5 binds directly with FYRN/FYRC domains of C-terminal SET domain-containing fragments of human KMT2C and KMT2D.<ref name="cho PTIP" /> UTX, the complex’s H3K27 demethylase, PTIP, and PA1 are subunits that are unique to KMT2C and KMT2D.<ref name="cho PTIP" /><ref name="cho 2012">{{cite journal | vauthors = Cho YW, Hong S, Ge K | title = Affinity purification of MLL3/MLL4 histone H3K4 methyltransferase complex | journal = Methods in Molecular Biology | volume = 809 | pages = 465–72 | date = 2012 | pmid = 22113294 | doi = 10.1007/978-1-61779-376-9_30 | pmc=3467094}}</ref><ref name="Hong UTX">{{cite journal | vauthors = Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K | title = Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 47 | pages = 18439–44 | date = November 2007 | pmid = 18003914 | doi = 10.1073/pnas.0707292104 | pmc=2141795}}</ref> KMT2D acts as a scaffold protein within the complex; absence of KMT2D results in destabilization of UTX and collapse of the complex in cells.<ref name="elife" /><ref name="jang YH" />


== Enhancer regulation ==  
== Enhancer regulation ==  
KMT2D is a major enhancer mono-methyltransferase and has partial functional redundancy with KMT2C.<ref name="elife" /><ref name="Wang 2016 enhancer priming" /> The protein selectively binds enhancer regions based on type of cell and stage of differentiation. During differentiation, lineage determining transcription factors recruit KMT2D to establish cell-type specific enhancers. For example, CCAAT/enhancer-binding protein β (C/EBPβ), an early adipogenic transcription factor, recruits and requires KMT2D to establish a subset of adipogenic enhancers during adipogenesis. Depletion of KMT2D prior to differentiation prevents the accumulation of H3K4 mono-methylation (H3K4me1), H3K27 acetylation, the transcriptional coactivator Mediator, and RNA polymerase II on enhancers, resulting in severe defects in gene expression and cell differentiation.<ref name="elife" /> KMT2C and KMT2D also identify super-enhancers and are required for formation of super-enhancers during cell differentiation.<ref name="lai 2017">{{cite journal | vauthors = Lai B, Lee JE, Jang Y, Wang L, Peng W, Ge K | title = MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis | journal = Nucleic Acids Research | date = April 2017 | pmid = 28398509 | doi = 10.1093/nar/gkx234 }}</ref> Mechanistically, KMT2C and KMT2D are required for the binding of H3K27 acetyltransferases CREB-binding protein (CBP) and/or p300 on enhancers, enhancer activation, and enhancer-promotor looping prior to gene transcription.<ref name="elife" /><ref name="lai 2017" /> Interestingly, the KMT2C and KMT2D proteins, rather than the KMT2C and KMT2D-mediated H3K4me1, control p300 recruitment to enhancers, enhancer activation, and transcription from promoters in embryonic stem cells.<ref name="Wang 2016 enhancer priming" />
KMT2D is a major enhancer mono-methyltransferase and has partial functional redundancy with KMT2C.<ref name="elife" /><ref name="Wang 2016 enhancer priming" /> The protein selectively binds enhancer regions based on type of cell and stage of differentiation. During differentiation, lineage determining transcription factors recruit KMT2D to establish cell-type specific enhancers. For example, CCAAT/enhancer-binding protein β (C/EBPβ), an early adipogenic transcription factor, recruits and requires KMT2D to establish a subset of adipogenic enhancers during adipogenesis. Depletion of KMT2D prior to differentiation prevents the accumulation of H3K4 mono-methylation (H3K4me1), H3K27 acetylation, the transcriptional coactivator Mediator, and RNA polymerase II on enhancers, resulting in severe defects in gene expression and cell differentiation.<ref name="elife" /> KMT2C and KMT2D also identify super-enhancers and are required for formation of super-enhancers during cell differentiation.<ref name="lai 2017">{{cite journal | vauthors = Lai B, Lee JE, Jang Y, Wang L, Peng W, Ge K | title = MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis | journal = Nucleic Acids Research | date = April 2017 | pmid = 28398509 | doi = 10.1093/nar/gkx234 | volume=45 | pmc=5499743 | pages=6388–6403}}</ref> Mechanistically, KMT2C and KMT2D are required for the binding of H3K27 acetyltransferases CREB-binding protein (CBP) and/or p300 on enhancers, enhancer activation, and enhancer-promotor looping prior to gene transcription.<ref name="elife" /><ref name="lai 2017" /> The KMT2C and KMT2D proteins, rather than the KMT2C and KMT2D-mediated H3K4me1, control p300 recruitment to enhancers, enhancer activation, and transcription from promoters in embryonic stem cells.<ref name="Wang 2016 enhancer priming" />


== Functions ==  
== Functions ==  
=== Development ===
=== Development ===
Whole-body knockout of ''Kmt2d'' in mice results in early embryonic lethality.<ref name="elife" /> Targeted knockout of ''Kmt2d'' in precursors cells of brown adipocytes and myocytes results in decreases in brown adipose tissue and muscle mass in mice, indicating that KMT2D is required for adipose and muscle tissue development.<ref name="elife" /> In the hearts of mice, a single copy of the ''Kmt2d'' gene is sufficient for normal heart development.<ref name="Ang heart development">{{cite journal | vauthors = Ang SY, Uebersohn A, Spencer CI, Huang Y, Lee JE, Ge K, Bruneau BG | title = KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation | journal = Development | volume = 143 | issue = 5 | pages = 810–21 | date = March 2016 | pmid = 26932671 | doi = 10.1242/dev.132688 }}</ref> Complete loss of ''Kmt2d'' in cardiac precursors and myocardium leads to severe cardiac defects and early embryonic lethality. KMT2D mediated mono- and di-methylation is required for maintaining necessary gene expression programs during heart development. Knockout studies in mice also show that KMT2D is required for proper B-cell development.<ref name="zhang 2015 B cell" />
Whole-body knockout of ''Kmt2d'' in mice results in early embryonic lethality.<ref name="elife" /> Targeted knockout of ''Kmt2d'' in precursors cells of brown adipocytes and myocytes results in decreases in brown adipose tissue and muscle mass in mice, indicating that KMT2D is required for adipose and muscle tissue development.<ref name="elife" /> In the hearts of mice, a single copy of the ''Kmt2d'' gene is sufficient for normal heart development.<ref name="Ang heart development">{{cite journal | vauthors = Ang SY, Uebersohn A, Spencer CI, Huang Y, Lee JE, Ge K, Bruneau BG | title = KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation | journal = Development | volume = 143 | issue = 5 | pages = 810–21 | date = March 2016 | pmid = 26932671 | doi = 10.1242/dev.132688 | pmc=4813342}}</ref> Complete loss of ''Kmt2d'' in cardiac precursors and myocardium leads to severe cardiac defects and early embryonic lethality. KMT2D mediated mono- and di-methylation is required for maintaining necessary gene expression programs during heart development. Knockout studies in mice also show that KMT2D is required for proper B-cell development.<ref name="zhang 2015 B cell" />


=== Cell fate transition ===
=== Cell fate transition ===
Line 28: Line 28:
KMT2C and KMT2D along with NCOA6 act as coactivators of p53, a well-established tumor suppressor and transcription factor, and are necessary for endogenous expression of p53 in response to doxorubicin, a DNA damaging agent.<ref name="lee 2009 p53" /> KMT2C and KMT2D have also been implicated with tumor suppressor roles in acute myeloid leukemia, follicular lymphoma, and diffuse large B cell lymphoma.<ref name="zhang 2015 B cell" /><ref name="chen 2014 mll3 tumor suppressor" /><ref name="ortega-molina" /> Knockout of ''Kmt2d'' in mice negatively affects the expression of tumor suppressor genes ''TNFAIP3'', ''SOCS3'', and ''TNFRSF14''.<ref name="ortega-molina" />  
KMT2C and KMT2D along with NCOA6 act as coactivators of p53, a well-established tumor suppressor and transcription factor, and are necessary for endogenous expression of p53 in response to doxorubicin, a DNA damaging agent.<ref name="lee 2009 p53" /> KMT2C and KMT2D have also been implicated with tumor suppressor roles in acute myeloid leukemia, follicular lymphoma, and diffuse large B cell lymphoma.<ref name="zhang 2015 B cell" /><ref name="chen 2014 mll3 tumor suppressor" /><ref name="ortega-molina" /> Knockout of ''Kmt2d'' in mice negatively affects the expression of tumor suppressor genes ''TNFAIP3'', ''SOCS3'', and ''TNFRSF14''.<ref name="ortega-molina" />  


Conversely, KMT2D deficiency in several breast and colon cancer cell lines leads to reduced proliferation.<ref>{{cite journal | vauthors = Guo C, Chen LH, Huang Y, Chang CC, Wang P, Pirozzi CJ, Qin X, Bao X, Greer PK, McLendon RE, Yan H, Keir ST, Bigner DD, He Y | display-authors = 6 | title = KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation | journal = Oncotarget | volume = 4 | issue = 11 | pages = 2144–53 | date = November 2013 | pmid = 24240169 | doi = 10.18632/oncotarget.1555 }}</ref><ref>{{cite journal | vauthors = Kim JH, Sharma A, Dhar SS, Lee SH, Gu B, Chan CH, Lin HK, Lee MG | title = UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells | journal = Cancer Research | volume = 74 | issue = 6 | pages = 1705–17 | date = March 2014 | pmid = 24491801 | doi = 10.1158/0008-5472.CAN-13-1896 }}</ref><ref>{{cite journal | vauthors = Mo R, Rao SM, Zhu YJ | title = Identification of the MLL2 complex as a coactivator for estrogen receptor alpha | journal = The Journal of Biological Chemistry | volume = 281 | issue = 23 | pages = 15714–20 | date = June 2006 | pmid = 16603732 | doi = 10.1074/jbc.M513245200 }}</ref> Increased KMT2D was shown to facilitate chromatin opening and recruitment of transcription factors, including estrogen receptor (ER), in ER-positive breast cancer cells.<ref>{{cite journal | vauthors = Toska E, Osmanbeyoglu HU, Castel P, Chan C, Hendrickson RC, Elkabets M, Dickler MN, Scaltriti M, Leslie CS, Armstrong SA, Baselga J | title = PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D | journal = Science | volume = 355 | issue = 6331 | pages = 1324–1330 | date = March 2017 | pmid = 28336670 | doi = 10.1126/science.aah6893 }}</ref> Thus, KMT2D may have diverse effects on tumor suppression in different cell types.
Conversely, KMT2D deficiency in several breast and colon cancer cell lines leads to reduced proliferation.<ref>{{cite journal | vauthors = Guo C, Chen LH, Huang Y, Chang CC, Wang P, Pirozzi CJ, Qin X, Bao X, Greer PK, McLendon RE, Yan H, Keir ST, Bigner DD, He Y | display-authors = 6 | title = KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation | journal = Oncotarget | volume = 4 | issue = 11 | pages = 2144–53 | date = November 2013 | pmid = 24240169 | doi = 10.18632/oncotarget.1555 | pmc=3875776}}</ref><ref>{{cite journal | vauthors = Kim JH, Sharma A, Dhar SS, Lee SH, Gu B, Chan CH, Lin HK, Lee MG | title = UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells | journal = Cancer Research | volume = 74 | issue = 6 | pages = 1705–17 | date = March 2014 | pmid = 24491801 | doi = 10.1158/0008-5472.CAN-13-1896 | pmc=3962500}}</ref><ref>{{cite journal | vauthors = Mo R, Rao SM, Zhu YJ | title = Identification of the MLL2 complex as a coactivator for estrogen receptor alpha | journal = The Journal of Biological Chemistry | volume = 281 | issue = 23 | pages = 15714–20 | date = June 2006 | pmid = 16603732 | doi = 10.1074/jbc.M513245200 }}</ref> Increased KMT2D was shown to facilitate chromatin opening and recruitment of transcription factors, including estrogen receptor (ER), in ER-positive breast cancer cells.<ref>{{cite journal | vauthors = Toska E, Osmanbeyoglu HU, Castel P, Chan C, Hendrickson RC, Elkabets M, Dickler MN, Scaltriti M, Leslie CS, Armstrong SA, Baselga J | title = PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D | journal = Science | volume = 355 | issue = 6331 | pages = 1324–1330 | date = March 2017 | pmid = 28336670 | doi = 10.1126/science.aah6893 | pmc=5485411}}</ref> Thus, KMT2D may have diverse effects on tumor suppression in different cell types.


== Clinical significance ==
== Clinical significance ==
Line 34: Line 34:
Loss of function mutations in KMT2D, also known as MLL2 in humans, have been identified in Kabuki syndrome,<ref name="Ng kabuki" /> with mutational occurrence rates between 56% and 75%.<ref>{{cite journal | vauthors = Bögershausen N, Wollnik B | title = Unmasking Kabuki syndrome | journal = Clinical Genetics | volume = 83 | issue = 3 | pages = 201–11 | date = March 2013 | pmid = 23131014 | doi = 10.1111/cge.12051 }}</ref><ref>{{cite journal | vauthors = Li Y, Bögershausen N, Alanay Y, Simsek Kiper PO, Plume N, Keupp K, Pohl E, Pawlik B, Rachwalski M, Milz E, Thoenes M, Albrecht B, Prott EC, Lehmkühler M, Demuth S, Utine GE, Boduroglu K, Frankenbusch K, Borck G, Gillessen-Kaesbach G, Yigit G, Wieczorek D, Wollnik B | display-authors = 6 | title = A mutation screen in patients with Kabuki syndrome | journal = Human Genetics | volume = 130 | issue = 6 | pages = 715–24 | date = December 2011 | pmid = 21607748 | doi = 10.1007/s00439-011-1004-y }}</ref><ref>{{cite journal | vauthors = Paulussen AD, Stegmann AP, Blok MJ, Tserpelis D, Posma-Velter C, Detisch Y, Smeets EE, Wagemans A, Schrander JJ, van den Boogaard MJ, van der Smagt J, van Haeringen A, Stolte-Dijkstra I, Kerstjens-Frederikse WS, Mancini GM, Wessels MW, Hennekam RC, Vreeburg M, Geraedts J, de Ravel T, Fryns JP, Smeets HJ, Devriendt K, Schrander-Stumpel CT | display-authors = 6 | title = MLL2 mutation spectrum in 45 patients with Kabuki syndrome | journal = Human Mutation | volume = 32 | issue = 2 | pages = E2018-25 | date = February 2011 | pmid = 21280141 | doi = 10.1002/humu.21416 }}</ref> Congenital heart disease has been associated with an excess of mutations in genes that regulate H3K4 methylation, including ''KMT2D''.<ref name="zaidi CHD" />
Loss of function mutations in KMT2D, also known as MLL2 in humans, have been identified in Kabuki syndrome,<ref name="Ng kabuki" /> with mutational occurrence rates between 56% and 75%.<ref>{{cite journal | vauthors = Bögershausen N, Wollnik B | title = Unmasking Kabuki syndrome | journal = Clinical Genetics | volume = 83 | issue = 3 | pages = 201–11 | date = March 2013 | pmid = 23131014 | doi = 10.1111/cge.12051 }}</ref><ref>{{cite journal | vauthors = Li Y, Bögershausen N, Alanay Y, Simsek Kiper PO, Plume N, Keupp K, Pohl E, Pawlik B, Rachwalski M, Milz E, Thoenes M, Albrecht B, Prott EC, Lehmkühler M, Demuth S, Utine GE, Boduroglu K, Frankenbusch K, Borck G, Gillessen-Kaesbach G, Yigit G, Wieczorek D, Wollnik B | display-authors = 6 | title = A mutation screen in patients with Kabuki syndrome | journal = Human Genetics | volume = 130 | issue = 6 | pages = 715–24 | date = December 2011 | pmid = 21607748 | doi = 10.1007/s00439-011-1004-y }}</ref><ref>{{cite journal | vauthors = Paulussen AD, Stegmann AP, Blok MJ, Tserpelis D, Posma-Velter C, Detisch Y, Smeets EE, Wagemans A, Schrander JJ, van den Boogaard MJ, van der Smagt J, van Haeringen A, Stolte-Dijkstra I, Kerstjens-Frederikse WS, Mancini GM, Wessels MW, Hennekam RC, Vreeburg M, Geraedts J, de Ravel T, Fryns JP, Smeets HJ, Devriendt K, Schrander-Stumpel CT | display-authors = 6 | title = MLL2 mutation spectrum in 45 patients with Kabuki syndrome | journal = Human Mutation | volume = 32 | issue = 2 | pages = E2018-25 | date = February 2011 | pmid = 21280141 | doi = 10.1002/humu.21416 }}</ref> Congenital heart disease has been associated with an excess of mutations in genes that regulate H3K4 methylation, including ''KMT2D''.<ref name="zaidi CHD" />


Frameshift and nonsense mutations in the SET and PHD domains affect 37% and 60%, respectively, of the total ''KMT2D'' mutations in cancers.<ref name="rao KMT2 review" /> Cancers with somatic mutations in ''KMT2D'' occur most commonly in the brain, lymph nodes, blood, lungs, large intestine, and endometrium.<ref name="rao KMT2 review" /> These cancers include medulloblastoma,<ref>{{cite journal | vauthors = Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, Carneiro MO, Carter SL, Cibulskis K, Erlich RL, Greulich H, Lawrence MS, Lennon NJ, McKenna A, Meldrim J, Ramos AH, Ross MG, Russ C, Shefler E, Sivachenko A, Sogoloff B, Stojanov P, Tamayo P, Mesirov JP, Amani V, Teider N, Sengupta S, Francois JP, Northcott PA, Taylor MD, Yu F, Crabtree GR, Kautzman AG, Gabriel SB, Getz G, Jäger N, Jones DT, Lichter P, Pfister SM, Roberts TM, Meyerson M, Pomeroy SL, Cho YJ | display-authors = 6 | title = Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations | journal = Nature | volume = 488 | issue = 7409 | pages = 106–10 | date = August 2012 | pmid = 22820256 | doi = 10.1038/nature11329 }}</ref><ref>{{cite journal | vauthors = Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC, Boca SM, Carter H, Samayoa J, Bettegowda C, Gallia GL, Jallo GI, Binder ZA, Nikolsky Y, Hartigan J, Smith DR, Gerhard DS, Fults DW, VandenBerg S, Berger MS, Marie SK, Shinjo SM, Clara C, Phillips PC, Minturn JE, Biegel JA, Judkins AR, Resnick AC, Storm PB, Curran T, He Y, Rasheed BA, Friedman HS, Keir ST, McLendon R, Northcott PA, Taylor MD, Burger PC, Riggins GJ, Karchin R, Parmigiani G, Bigner DD, Yan H, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE | display-authors = 6 | title = The genetic landscape of the childhood cancer medulloblastoma | journal = Science | volume = 331 | issue = 6016 | pages = 435–9 | date = January 2011 | pmid = 21163964 | doi = 10.1126/science.1198056 }}</ref><ref>{{cite journal | vauthors = Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schüller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann MU, Frühwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P | display-authors = 6 | title = Dissecting the genomic complexity underlying medulloblastoma | journal = Nature | volume = 488 | issue = 7409 | pages = 100–5 | date = August 2012 | pmid = 22832583 | doi = 10.1038/nature11284 }}</ref> pheochromocytoma,<ref>{{cite journal | vauthors = Juhlin CC, Stenman A, Haglund F, Clark VE, Brown TC, Baranoski J, Bilguvar K, Goh G, Welander J, Svahn F, Rubinstein JC, Caramuta S, Yasuno K, Günel M, Bäckdahl M, Gimm O, Söderkvist P, Prasad ML, Korah R, Lifton RP, Carling T | display-authors = 6 | title = Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene | journal = Genes, Chromosomes & Cancer | volume = 54 | issue = 9 | pages = 542–54 | date = September 2015 | pmid = 26032282 | doi = 10.1002/gcc.22267 }}</ref> non-Hodgkin lymphoma,<ref>{{cite journal | vauthors = Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJ, Connors JM, Hirst M, Gascoyne RD, Marra MA  | display-authors = 6  | title = Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma | journal = Nature | volume = 476 | issue = 7360 | pages = 298–303 | date = July 2011 | pmid = 21796119 | doi = 10.1038/nature10351 }}</ref> diffuse large B-cell lymphoma,<ref>{{cite journal | vauthors = Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, Wells VA, Grunn A, Messina M, Elliot O, Chan J, Bhagat G, Chadburn A, Gaidano G, Mullighan CG, Rabadan R, Dalla-Favera R | title = Analysis of the coding genome of diffuse large B-cell lymphoma | journal = Nature Genetics | volume = 43 | issue = 9 | pages = 830–7 | date = July 2011 | pmid = 21804550 | doi = 10.1038/ng.892 }}</ref><ref>{{cite journal | vauthors = Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, Cruz-Gordillo P, Knoechel B, Asmann YW, Slager SL, Novak AJ, Dogan A, Ansell SM, Link BK, Zou L, Gould J, Saksena G, Stransky N, Rangel-Escareño C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Hernández-Lemus E, Schwarz-Cruz y Celis A, Imaz-Rosshandler I, Ojesina AI, Jung J, Pedamallu CS, Lander ES, Habermann TM, Cerhan JR, Shipp MA, Getz G, Golub TR  | display-authors = 6  | title = Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 10 | pages = 3879–84 | date = March 2012 | pmid = 22343534 | doi = 10.1073/pnas.1121343109 }}</ref> cutaneous T-cell lymphoma, Sézary syndrome,<ref>{{cite journal | vauthors = da Silva Almeida AC, Abate F, Khiabanian H, Martinez-Escala E, Guitart J, Tensen CP, Vermeer MH, Rabadan R, Ferrando A, Palomero T | title = The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome | journal = Nature Genetics | volume = 47 | issue = 12 | pages = 1465–70 | date = December 2015 | pmid = 26551667 | doi = 10.1038/ng.3442 }}</ref> bladder, lung, and endometrial carcinomas,<ref>{{cite journal | vauthors = Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MD, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L | display-authors = 6 | title = Mutational landscape and significance across 12 major cancer types | journal = Nature | volume = 502 | issue = 7471 | pages = 333–9 | date = October 2013 | pmid = 24132290 | doi = 10.1038/nature12634 }}</ref> esophageal squamous cell carcinoma,<ref>{{cite journal | vauthors = Gao YB, Chen ZL, Li JG, Hu XD, Shi XJ, Sun ZM, Zhang F, Zhao ZR, Li ZT, Liu ZY, Zhao YD, Sun J, Zhou CC, Yao R, Wang SY, Wang P, Sun N, Zhang BH, Dong JS, Yu Y, Luo M, Feng XL, Shi SS, Zhou F, Tan FW, Qiu B, Li N, Shao K, Zhang LJ, Zhang LJ, Xue Q, Gao SG, He J | display-authors = 6 | title = Genetic landscape of esophageal squamous cell carcinoma | journal = Nature Genetics | volume = 46 | issue = 10 | pages = 1097–102 | date = October 2014 | pmid = 25151357 | doi = 10.1038/ng.3076 }}</ref><ref>{{cite journal | vauthors = Lin DC, Hao JJ, Nagata Y, Xu L, Shang L, Meng X, Sato Y, Okuno Y, Varela AM, Ding LW, Garg M, Liu LZ, Yang H, Yin D, Shi ZZ, Jiang YY, Gu WY, Gong T, Zhang Y, Xu X, Kalid O, Shacham S, Ogawa S, Wang MR, Koeffler HP | title = Genomic and molecular characterization of esophageal squamous cell carcinoma | journal = Nature Genetics | volume = 46 | issue = 5 | pages = 467–73 | date = May 2014 | pmid = 24686850 | doi = 10.1038/ng.2935 }}</ref><ref>{{cite journal | vauthors = Song Y, Li L, Ou Y, Gao Z, Li E, Li X, Zhang W, Wang J, Xu L, Zhou Y, Ma X, Liu L, Zhao Z, Huang X, Fan J, Dong L, Chen G, Ma L, Yang J, Chen L, He M, Li M, Zhuang X, Huang K, Qiu K, Yin G, Guo G, Feng Q, Chen P, Wu Z, Wu J, Ma L, Zhao J, Luo L, Fu M, Xu B, Chen B, Li Y, Tong T, Wang M, Liu Z, Lin D, Zhang X, Yang H, Wang J, Zhan Q | display-authors = 6 | title = Identification of genomic alterations in oesophageal squamous cell cancer | journal = Nature | volume = 509 | issue = 7498 | pages = 91–5 | date = May 2014 | pmid = 24670651 | doi = 10.1038/nature13176 }}</ref> pancreatic cancer,<ref>{{cite journal | vauthors = Sausen M, Phallen J, Adleff V, Jones S, Leary RJ, Barrett MT, Anagnostou V, Parpart-Li S, Murphy D, Kay Li Q, Hruban CA, Scharpf R, White JR, O'Dwyer PJ, Allen PJ, Eshleman JR, Thompson CB, Klimstra DS, Linehan DC, Maitra A, Hruban RH, Diaz LA, Von Hoff DD, Johansen JS, Drebin JA, Velculescu VE | title = Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients | display-authors = 6 | journal = Nature Communications | volume = 6 | pages = 7686 | date = July 2015 | pmid = 26154128 | doi = 10.1038/ncomms8686 }}</ref> and prostate cancer.<ref>{{cite journal | vauthors = Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, Quist MJ, Jing X, Lonigro RJ, Brenner JC, Asangani IA, Ateeq B, Chun SY, Siddiqui J, Sam L, Anstett M, Mehra R, Prensner JR, Palanisamy N, Ryslik GA, Vandin F, Raphael BJ, Kunju LP, Rhodes DR, Pienta KJ, Chinnaiyan AM, Tomlins SA | display-authors = 6 | title = The mutational landscape of lethal castration-resistant prostate cancer | journal = Nature | volume = 487 | issue = 7406 | pages = 239–43 | date = July 2012 | pmid = 22722839 | doi = 10.1038/nature11125 }}</ref>
Frameshift and nonsense mutations in the SET and PHD domains affect 37% and 60%, respectively, of the total ''KMT2D'' mutations in cancers.<ref name="rao KMT2 review" /> Cancers with somatic mutations in ''KMT2D'' occur most commonly in the brain, lymph nodes, blood, lungs, large intestine, and endometrium.<ref name="rao KMT2 review" /> These cancers include medulloblastoma,<ref>{{cite journal | vauthors = Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, Carneiro MO, Carter SL, Cibulskis K, Erlich RL, Greulich H, Lawrence MS, Lennon NJ, McKenna A, Meldrim J, Ramos AH, Ross MG, Russ C, Shefler E, Sivachenko A, Sogoloff B, Stojanov P, Tamayo P, Mesirov JP, Amani V, Teider N, Sengupta S, Francois JP, Northcott PA, Taylor MD, Yu F, Crabtree GR, Kautzman AG, Gabriel SB, Getz G, Jäger N, Jones DT, Lichter P, Pfister SM, Roberts TM, Meyerson M, Pomeroy SL, Cho YJ | display-authors = 6 | title = Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations | journal = Nature | volume = 488 | issue = 7409 | pages = 106–10 | date = August 2012 | pmid = 22820256 | doi = 10.1038/nature11329 | pmc=3413789}}</ref><ref>{{cite journal | vauthors = Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC, Boca SM, Carter H, Samayoa J, Bettegowda C, Gallia GL, Jallo GI, Binder ZA, Nikolsky Y, Hartigan J, Smith DR, Gerhard DS, Fults DW, VandenBerg S, Berger MS, Marie SK, Shinjo SM, Clara C, Phillips PC, Minturn JE, Biegel JA, Judkins AR, Resnick AC, Storm PB, Curran T, He Y, Rasheed BA, Friedman HS, Keir ST, McLendon R, Northcott PA, Taylor MD, Burger PC, Riggins GJ, Karchin R, Parmigiani G, Bigner DD, Yan H, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE | display-authors = 6 | title = The genetic landscape of the childhood cancer medulloblastoma | journal = Science | volume = 331 | issue = 6016 | pages = 435–9 | date = January 2011 | pmid = 21163964 | doi = 10.1126/science.1198056 | pmc = 3110744 }}</ref><ref>{{cite journal | vauthors = Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schüller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann MU, Frühwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P | display-authors = 6 | title = Dissecting the genomic complexity underlying medulloblastoma | journal = Nature | volume = 488 | issue = 7409 | pages = 100–5 | date = August 2012 | pmid = 22832583 | doi = 10.1038/nature11284 | pmc=3662966}}</ref> pheochromocytoma,<ref>{{cite journal | vauthors = Juhlin CC, Stenman A, Haglund F, Clark VE, Brown TC, Baranoski J, Bilguvar K, Goh G, Welander J, Svahn F, Rubinstein JC, Caramuta S, Yasuno K, Günel M, Bäckdahl M, Gimm O, Söderkvist P, Prasad ML, Korah R, Lifton RP, Carling T | display-authors = 6 | title = Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene | journal = Genes, Chromosomes & Cancer | volume = 54 | issue = 9 | pages = 542–54 | date = September 2015 | pmid = 26032282 | doi = 10.1002/gcc.22267 | pmc=4755142}}</ref> non-Hodgkin lymphomas,<ref>{{cite journal | vauthors = Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJ, Connors JM, Hirst M, Gascoyne RD, Marra MA  | display-authors = 6  | title = Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma | journal = Nature | volume = 476 | issue = 7360 | pages = 298–303 | date = July 2011 | pmid = 21796119 | doi = 10.1038/nature10351 | pmc=3210554}}</ref>, cutaneous T-cell lymphoma, Sézary syndrome,<ref>{{cite journal | vauthors = da Silva Almeida AC, Abate F, Khiabanian H, Martinez-Escala E, Guitart J, Tensen CP, Vermeer MH, Rabadan R, Ferrando A, Palomero T | title = The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome | journal = Nature Genetics | volume = 47 | issue = 12 | pages = 1465–70 | date = December 2015 | pmid = 26551667 | doi = 10.1038/ng.3442 | pmc=4878831}}</ref> bladder, lung, and endometrial carcinomas,<ref>{{cite journal | vauthors = Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MD, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L | display-authors = 6 | title = Mutational landscape and significance across 12 major cancer types | journal = Nature | volume = 502 | issue = 7471 | pages = 333–9 | date = October 2013 | pmid = 24132290 | doi = 10.1038/nature12634 | pmc=3927368}}</ref> esophageal squamous cell carcinoma,<ref>{{cite journal | vauthors = Gao YB, Chen ZL, Li JG, Hu XD, Shi XJ, Sun ZM, Zhang F, Zhao ZR, Li ZT, Liu ZY, Zhao YD, Sun J, Zhou CC, Yao R, Wang SY, Wang P, Sun N, Zhang BH, Dong JS, Yu Y, Luo M, Feng XL, Shi SS, Zhou F, Tan FW, Qiu B, Li N, Shao K, Zhang LJ, Zhang LJ, Xue Q, Gao SG, He J | display-authors = 6 | title = Genetic landscape of esophageal squamous cell carcinoma | journal = Nature Genetics | volume = 46 | issue = 10 | pages = 1097–102 | date = October 2014 | pmid = 25151357 | doi = 10.1038/ng.3076 }}</ref><ref>{{cite journal | vauthors = Lin DC, Hao JJ, Nagata Y, Xu L, Shang L, Meng X, Sato Y, Okuno Y, Varela AM, Ding LW, Garg M, Liu LZ, Yang H, Yin D, Shi ZZ, Jiang YY, Gu WY, Gong T, Zhang Y, Xu X, Kalid O, Shacham S, Ogawa S, Wang MR, Koeffler HP | title = Genomic and molecular characterization of esophageal squamous cell carcinoma | journal = Nature Genetics | volume = 46 | issue = 5 | pages = 467–73 | date = May 2014 | pmid = 24686850 | doi = 10.1038/ng.2935 | pmc=4070589}}</ref><ref>{{cite journal | vauthors = Song Y, Li L, Ou Y, Gao Z, Li E, Li X, Zhang W, Wang J, Xu L, Zhou Y, Ma X, Liu L, Zhao Z, Huang X, Fan J, Dong L, Chen G, Ma L, Yang J, Chen L, He M, Li M, Zhuang X, Huang K, Qiu K, Yin G, Guo G, Feng Q, Chen P, Wu Z, Wu J, Ma L, Zhao J, Luo L, Fu M, Xu B, Chen B, Li Y, Tong T, Wang M, Liu Z, Lin D, Zhang X, Yang H, Wang J, Zhan Q | display-authors = 6 | title = Identification of genomic alterations in oesophageal squamous cell cancer | journal = Nature | volume = 509 | issue = 7498 | pages = 91–5 | date = May 2014 | pmid = 24670651 | doi = 10.1038/nature13176 }}</ref> pancreatic cancer,<ref>{{cite journal | vauthors = Sausen M, Phallen J, Adleff V, Jones S, Leary RJ, Barrett MT, Anagnostou V, Parpart-Li S, Murphy D, Kay Li Q, Hruban CA, Scharpf R, White JR, O'Dwyer PJ, Allen PJ, Eshleman JR, Thompson CB, Klimstra DS, Linehan DC, Maitra A, Hruban RH, Diaz LA, Von Hoff DD, Johansen JS, Drebin JA, Velculescu VE | title = Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients | display-authors = 6 | journal = Nature Communications | volume = 6 | pages = 7686 | date = July 2015 | pmid = 26154128 | doi = 10.1038/ncomms8686 | pmc=4634573}}</ref> and prostate cancer.<ref>{{cite journal | vauthors = Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, Quist MJ, Jing X, Lonigro RJ, Brenner JC, Asangani IA, Ateeq B, Chun SY, Siddiqui J, Sam L, Anstett M, Mehra R, Prensner JR, Palanisamy N, Ryslik GA, Vandin F, Raphael BJ, Kunju LP, Rhodes DR, Pienta KJ, Chinnaiyan AM, Tomlins SA | display-authors = 6 | title = The mutational landscape of lethal castration-resistant prostate cancer | journal = Nature | volume = 487 | issue = 7406 | pages = 239–43 | date = July 2012 | pmid = 22722839 | doi = 10.1038/nature11125 | pmc=3396711}}</ref>


==Notes==
==Notes==

Latest revision as of 13:27, 4 November 2018

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Identifiers
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Orthologs
SpeciesHumanMouse
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Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase.[1] It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A (or MLL1), KMT2B (or MLL2), KMT2C (or MLL3), KMT2F (or SET1A), and KMT2G (or SET1B). KMT2D is a large protein over 5,500 amino acids in size and is widely expressed in adult tissues.[2] The protein co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development.[1] It also plays critical roles in regulating cell fate transition,[1][3][4][5] metabolism,[6][7] and tumor suppression.[8][9][10][11] Mutations in KMT2D have been associated with Kabuki Syndrome,[12] congenital heart disease,[13] and various forms of cancer.[14]

Structure

Gene

In mice, KMT2D is coded by the Kmt2d gene located on chromosome 15F1. Its transcript is 19,823 base pairs long and contains 55 exons and 54 introns.[15] In humans, KMT2D is coded by the KMT2D gene located on chromosome 12q13.12. Its transcript is 19,419 base pairs long and contains 54 exons and 53 introns.[16]

Protein

KMT2D is homologous to Trithorax-related (Trr), which is a Trithorax-group protein.[17] The mouse and human KMT2D proteins are 5,588 and 5,537 amino acids in length, respectively. Both species of the protein weigh about 600 kDa.[15][16] KMT2D contains an enzymatically active C-terminal SET domain that is responsible for its methyltransferase activity and maintaining protein stability in cells.[18] Near the SET domain are a plant homeotic domain (PHD) and FY-rich N/C-terminal (FYRN and FYRC) domains. The protein also contains six N-terminal PHDs, a high mobility group (HMG-I), and nine nuclear receptor interacting motifs (LXXLLs).[14] It was shown that amino acids Y5426 and Y5512 are critical for the enzymatic activity of human KMT2D in vitro.[19] In addition, mutation of Y5477 in mouse KMT2D, which corresponds to Y5426 in human KMT2D, resulted in the inactivation of KMT2D's enzymatic activity in embryonic stem cells.[20] Depletion of cellular H3K4 methylation reduces KMT2D levels, indicating that the protein's stability could be regulated by cellular H3K4 methylation.[19]

Protein complex

Several components of the KMT2D complex were first purified in 2003,[21] and then the entire complex was identified in 2007.[22][23][24][25] Along with KMT2D, the complex also contains ASH2L, RbBP5, WDR5, DPY30, NCOA6, UTX (also known as KDM6A), PA1, and PTIP. WDR5, RbBP5, ASH2L, and DPY30 form the four-subunit sub-complex WRAD, which is critical for H3K4 methyltransferase activity in all mammalian Set1-like histone methyltransferase complexes.[26] WDR5 binds directly with FYRN/FYRC domains of C-terminal SET domain-containing fragments of human KMT2C and KMT2D.[22] UTX, the complex’s H3K27 demethylase, PTIP, and PA1 are subunits that are unique to KMT2C and KMT2D.[22][27][28] KMT2D acts as a scaffold protein within the complex; absence of KMT2D results in destabilization of UTX and collapse of the complex in cells.[1][19]

Enhancer regulation

KMT2D is a major enhancer mono-methyltransferase and has partial functional redundancy with KMT2C.[1][3] The protein selectively binds enhancer regions based on type of cell and stage of differentiation. During differentiation, lineage determining transcription factors recruit KMT2D to establish cell-type specific enhancers. For example, CCAAT/enhancer-binding protein β (C/EBPβ), an early adipogenic transcription factor, recruits and requires KMT2D to establish a subset of adipogenic enhancers during adipogenesis. Depletion of KMT2D prior to differentiation prevents the accumulation of H3K4 mono-methylation (H3K4me1), H3K27 acetylation, the transcriptional coactivator Mediator, and RNA polymerase II on enhancers, resulting in severe defects in gene expression and cell differentiation.[1] KMT2C and KMT2D also identify super-enhancers and are required for formation of super-enhancers during cell differentiation.[29] Mechanistically, KMT2C and KMT2D are required for the binding of H3K27 acetyltransferases CREB-binding protein (CBP) and/or p300 on enhancers, enhancer activation, and enhancer-promotor looping prior to gene transcription.[1][29] The KMT2C and KMT2D proteins, rather than the KMT2C and KMT2D-mediated H3K4me1, control p300 recruitment to enhancers, enhancer activation, and transcription from promoters in embryonic stem cells.[3]

Functions

Development

Whole-body knockout of Kmt2d in mice results in early embryonic lethality.[1] Targeted knockout of Kmt2d in precursors cells of brown adipocytes and myocytes results in decreases in brown adipose tissue and muscle mass in mice, indicating that KMT2D is required for adipose and muscle tissue development.[1] In the hearts of mice, a single copy of the Kmt2d gene is sufficient for normal heart development.[30] Complete loss of Kmt2d in cardiac precursors and myocardium leads to severe cardiac defects and early embryonic lethality. KMT2D mediated mono- and di-methylation is required for maintaining necessary gene expression programs during heart development. Knockout studies in mice also show that KMT2D is required for proper B-cell development.[8]

Cell fate transition

KMT2D is partially functionally redundant with KMT2C and is required for cell differentiation in culture.[1][3] KMT2D regulates the induction of adipogenic and myogenic genes and is required for cell-type specific gene expression during differentiation. KMT2C and KMT2D are essential for adipogenesis and myogenesis.[1] Similar functions are seen in neuronal and osteoblast differentiation.[4][5] KMT2D facilitates cell fate transition by priming enhancers (through H3K4me1) for p300-mediated activation. For p300 to bind the enhancer, the physical presence of KMT2D, and not just the KMT2D-mediated H3K4me1, is required. However, KMT2D is dispensable for maintaining embryonic stem cell and somatic cell identity.[3]

Metabolism

KMT2D is partially functionally redundant with KMT2C in the liver as well. Heterozygous Kmt2d+/- mice exhibit enhanced glucose tolerance and insulin sensitivity and increased serum bile acid.[6] KMT2C and KMT2D are significant epigenetic regulators of the hepatic circadian clock and are co-activators of the circadian transcription factors retinoid-related orphan receptor (ROR)-α and -γ.[6] In mice, KMT2D also acts as a coactivator of PPARγ within the liver to direct over-nutrition induced steatosis. Heterozygous Kmt2d+/- mice exhibit resistance to over-nutrition induced hepatic steatosis.[7]

Tumor suppression

KMT2C and KMT2D along with NCOA6 act as coactivators of p53, a well-established tumor suppressor and transcription factor, and are necessary for endogenous expression of p53 in response to doxorubicin, a DNA damaging agent.[9] KMT2C and KMT2D have also been implicated with tumor suppressor roles in acute myeloid leukemia, follicular lymphoma, and diffuse large B cell lymphoma.[8][10][11] Knockout of Kmt2d in mice negatively affects the expression of tumor suppressor genes TNFAIP3, SOCS3, and TNFRSF14.[11]

Conversely, KMT2D deficiency in several breast and colon cancer cell lines leads to reduced proliferation.[31][32][33] Increased KMT2D was shown to facilitate chromatin opening and recruitment of transcription factors, including estrogen receptor (ER), in ER-positive breast cancer cells.[34] Thus, KMT2D may have diverse effects on tumor suppression in different cell types.

Clinical significance

Loss of function mutations in KMT2D, also known as MLL2 in humans, have been identified in Kabuki syndrome,[12] with mutational occurrence rates between 56% and 75%.[35][36][37] Congenital heart disease has been associated with an excess of mutations in genes that regulate H3K4 methylation, including KMT2D.[13]

Frameshift and nonsense mutations in the SET and PHD domains affect 37% and 60%, respectively, of the total KMT2D mutations in cancers.[14] Cancers with somatic mutations in KMT2D occur most commonly in the brain, lymph nodes, blood, lungs, large intestine, and endometrium.[14] These cancers include medulloblastoma,[38][39][40] pheochromocytoma,[41] non-Hodgkin lymphomas,[42], cutaneous T-cell lymphoma, Sézary syndrome,[43] bladder, lung, and endometrial carcinomas,[44] esophageal squamous cell carcinoma,[45][46][47] pancreatic cancer,[48] and prostate cancer.[49]

Notes


References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Lee JE, Wang C, Xu S, Cho YW, Wang L, Feng X, et al. (December 2013). "H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation". eLife. 2: e01503. doi:10.7554/eLife.01503. PMC 3869375. PMID 24368734.
  2. ↑ Prasad R, Zhadanov AB, Sedkov Y, Bullrich F, Druck T, Rallapalli R, et al. (July 1997). "Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax". Oncogene. 15 (5): 549–60. doi:10.1038/sj.onc.1201211. PMID 9247308.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Wang C, Lee JE, Lai B, Macfarlan TS, Xu S, Zhuang L, Liu C, Peng W, Ge K (October 2016). "Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition". Proceedings of the National Academy of Sciences of the United States of America. 113 (42): 11871–11876. doi:10.1073/pnas.1606857113. PMC 5081576. PMID 27698142.
  4. ↑ 4.0 4.1 Dhar SS, Lee SH, Kan PY, Voigt P, Ma L, Shi X, Reinberg D, Lee MG (December 2012). "Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4". Genes & Development. 26 (24): 2749–62. doi:10.1101/gad.203356.112. PMC 3533079. PMID 23249737.
  5. ↑ 5.0 5.1 Munehira Y, Yang Z, Gozani O (October 2016). "Systematic Analysis of Known and Candidate Lysine Demethylases in the Regulation of Myoblast Differentiation". Journal of Molecular Biology. 429: 2055–2065. doi:10.1016/j.jmb.2016.10.004. PMC 5388604. PMID 27732873.
  6. ↑ 6.0 6.1 6.2 Kim DH, Rhee JC, Yeo S, Shen R, Lee SK, Lee JW, Lee S (March 2015). "Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice". Hepatology. 61 (3): 1012–23. doi:10.1002/hep.27578. PMC 4474368. PMID 25346535.
  7. ↑ 7.0 7.1 Kim DH, Kim J, Kwon JS, Sandhu J, Tontonoz P, Lee SK, Lee S, Lee JW (November 2016). "Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2". Cell Reports. 17 (6): 1671–1682. doi:10.1016/j.celrep.2016.10.023. PMID 27806304.
  8. ↑ 8.0 8.1 8.2 Zhang J, Dominguez-Sola D, Hussein S, Lee JE, Holmes AB, Bansal M, et al. (October 2015). "Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis". Nature Medicine. 21 (10): 1190–8. doi:10.1038/nm.3940. PMC 5145002. PMID 26366712.
  9. ↑ 9.0 9.1 Lee J, Kim DH, Lee S, Yang QH, Lee DK, Lee SK, Roeder RG, Lee JW (May 2009). "A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4". Proceedings of the National Academy of Sciences of the United States of America. 106 (21): 8513–8. doi:10.1073/pnas.0902873106. PMC 2689008. PMID 19433796.
  10. ↑ 10.0 10.1 Chen C, Liu Y, Rappaport AR, Kitzing T, Schultz N, Zhao Z, Shroff AS, Dickins RA, Vakoc CR, Bradner JE, Stock W, LeBeau MM, Shannon KM, Kogan S, Zuber J, Lowe SW (May 2014). "MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia". Cancer Cell. 25 (5): 652–65. doi:10.1016/j.ccr.2014.03.016. PMC 4206212. PMID 24794707.
  11. ↑ 11.0 11.1 11.2 Ortega-Molina A, Boss IW, Canela A, Pan H, Jiang Y, Zhao C, et al. (October 2015). "The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development". Nature Medicine. 21 (10): 1199–208. doi:10.1038/nm.3943. PMC 4676270. PMID 26366710.
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  13. ↑ 13.0 13.1 Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, et al. (June 2013). "De novo mutations in histone-modifying genes in congenital heart disease" (PDF). Nature. 498 (7453): 220–3. doi:10.1038/nature12141. PMC 3706629. PMID 23665959.
  14. ↑ 14.0 14.1 14.2 14.3 Rao RC, Dou Y (June 2015). "Hijacked in cancer: the KMT2 (MLL) family of methyltransferases". Nature Reviews. Cancer. 15 (6): 334–46. doi:10.1038/nrc3929. PMC 4493861. PMID 25998713.
  15. ↑ 15.0 15.1 "Transcript: Kmt2d-001 (ENSMUST00000023741.15) - Summary - Mus musculus - Ensembl genome browser 88". www.ensembl.org.
  16. ↑ 16.0 16.1 "Transcript: KMT2D-001 (ENST00000301067.11) - Summary - Homo sapiens - Ensembl genome browser 88". www.ensembl.org.
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  19. ↑ 19.0 19.1 19.2 Jang Y, Wang C, Zhuang L, Liu C, Ge K (December 2016). "H3K4 Methyltransferase Activity Is Required for MLL4 Protein Stability". Journal of Molecular Biology. 429: 2046–2054. doi:10.1016/j.jmb.2016.12.016. PMC 5474351. PMID 28013028.
  20. ↑ Dorighi KM, Swigut T, Henriques T, Bhanu NV, Scruggs BS, Nady N, Still CD, Garcia BA, Adelman K, Wysocka J (May 2017). "Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation". Molecular Cell. 66: 568–576.e4. doi:10.1016/j.molcel.2017.04.018. PMC 5662137. PMID 28483418.
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