The BCL11A gene encodes for a regulatory C2H2 type zinc-finger protein, that can bind to the DNA. Five alternatively spliced transcript variants of this gene, which encode distinct isoforms, have been reported.[3] The protein associates with the SWI/SNF complex, that regulates gene expression via chromatin remodelling.[4]
BCL11A is highly expressed in several hematopoietic lineages, and plays a role in the switch from γ- to β-globin expression during the fetal to adult erythropoiesis transition.[5]
Furthermore, BCL11A is expressed in the brain, where it forms a protein complex with CASK to regulate axon outgrowth and branching.[6] In the neocortex, BCL11A binds to the TBR1 regulatory region and inhibits the expression of TBR1.[7]
Clinical significance
The corresponding Bcl11a mouse gene is a common site of retroviral integration in myeloid leukemia, and may function as a leukemia disease gene, in part, through its interaction with BCL6. During hematopoietic cell differentiation, this gene is down-regulated. It is possibly involved in lymphoma pathogenesis since translocations associated with B-cell malignancies also deregulates its expression. In addition, BCL11A has been found to play a role in the suppression of fetal hemoglobin production. Therapeutic strategies aimed at increasing fetal globin production in diseases such as beta thalassemia and sickle cell anemia by inhibiting BCL11A are currently being explored.
Furthermore, heterozygous de novo mutations in BCL11A have been identified in an intellectual disability disorder, accompanied with global developmental delay and autism spectrum disorder.[8] These mutations disrupt BCL11A homodimerization and transcriptional regulation.
Interactions
BCL11A has been shown to interact with a number of proteins. BCL11A was initially discovered as a COUP-TFI interacting protein.[9] In the nucleus, BCL11A forms paraspeckles that co-localize with NONO.[8] In neurons, BCL11A interacts with CASK to regulate target genes.[6] Furthermore, BCL11A interacts with the neuron-specific protein TBR1, which is also implicated in intellectual disability and autism spectrum disorder.[10]
References
↑Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola EL, Liu H, Price HP, Gesk S, Steinemann D, Schlegelberger B, Oscier DG, Siebert R, Tucker PW, Dyer MJ (December 2001). "The BCL11 gene family: involvement of BCL11A in lymphoid malignancies". Blood. 98 (12): 3413–20. doi:10.1182/blood.V98.12.3413. PMID11719382.
↑ 6.06.1Kuo TY, Hong CJ, Chien HL, Hsueh YP (August 2010). "X-linked mental retardation gene CASK interacts with Bcl11A/CTIP1 and regulates axon branching and outgrowth". Journal of Neuroscience Research (in Deutsch). 88 (11): 2364–73. doi:10.1002/jnr.22407. PMID20623620.
↑Cánovas J, Berndt FA, Sepúlveda H, Aguilar R, Veloso FA, Montecino M, Oliva C, Maass JC, Sierralta J, Kukuljan M (May 2015). "The Specification of Cortical Subcerebral Projection Neurons Depends on the Direct Repression of TBR1 by CTIP1/BCL11a". The Journal of Neuroscience. 35 (19): 7552–64. doi:10.1523/JNEUROSCI.0169-15.2015. PMID25972180.
Saiki Y, Yamazaki Y, Yoshida M, Katoh O, Nakamura T (December 2000). "Human EVI9, a homologue of the mouse myeloid leukemia gene, is expressed in the hematopoietic progenitors and down-regulated during myeloid differentiation of HL60 cells". Genomics. 70 (3): 387–91. doi:10.1006/geno.2000.6385. PMID11161790.
Nagase T, Nakayama M, Nakajima D, Kikuno R, Ohara O (April 2001). "Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 8 (2): 85–95. doi:10.1093/dnares/8.2.85. PMID11347906.
Martín-Subero JI, Gesk S, Harder L, Sonoki T, Tucker PW, Schlegelberger B, Grote W, Novo FJ, Calasanz MJ, Hansmann ML, Dyer MJ, Siebert R (February 2002). "Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma". Blood. 99 (4): 1474–7. doi:10.1182/blood.V99.4.1474. PMID11830502.
Küppers R, Sonoki T, Satterwhite E, Gesk S, Harder L, Oscier DG, Tucker PW, Dyer MJ, Siebert R (May 2002). "Lack of somatic hypermutation of IG V(H) genes in lymphoid malignancies with t(2;14)(p13;q32) translocation involving the BCL11A gene". Leukemia. 16 (5): 937–9. doi:10.1038/sj.leu.2402480. PMID11986957.
