E2 box gene transcriptions

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Editor-In-Chief: Henry A. Hoff

"The most dramatic impact on immunoglobulin gene enhancer activity was observed upon mutation of sites that contain an E2-box motif (G/ACAGNTGN)."[1]

"The E box sites that are most important are those of the E2 box class (GCAGXTGG/T). Two E2 box sites are present in the immunoglobulin heavy chain gene enhancer, p.E2 and /~E5, and one is present in the kappa enhancer, designated KE2 [29-31]."[2]

Cadherins

"Transcriptional downregulation of E-cadherin appears to be an important event in the progression of various epithelial tumors. SIP1 (ZEB-2) is a Smad-interacting, multi-zinc finger protein that shows specific DNA binding activity. [Expression] of wild-type but not of mutated SIP1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadherin promoter."[3]

"Analysis of mouse and human E-cadherin promoters revealed a conserved modular structure with positive regulatory elements including two E2 boxes (CACCTG) with a potential repressor role Behrens et al. 1991, Giroldi et al. 1997."[3]

"The two E2 boxes in the mouse and human E-cadherin promoter sequences were demonstrated to play a crucial role in the epithelial-specific expression of E-cadherin Behrens et al. 1991, Giroldi et al. 1997. Mutation of these sequence elements results in upregulation of the E-cadherin promoter in dedifferentiated cancer cells, whereas the wild-type promoter shows low activity in such cells. Recently, it was shown that the zinc finger transcriptional repressor Snail can downregulate E-cadherin by binding to the E boxes in the E-cadherin promoter Batlle et al. 2000, Cano et al. 2000. Human Snail belongs to a family of zinc finger proteins, which contain four or five zinc finger domains of the C2H2 type at their C-terminal end. These zinc fingers bind to the CANNTG sequence in E box motifs."[3]

"δEF1 and SIP1 have been shown to bind spaced CACCT DNA sequences, including E2 boxes (CACCTG), by their zinc finger clusters (Remacle et al., 1999)."[3]

"To address the specificity of SIP1 action, mutagenesis of the E-cadherin promoter in either its upstream E2 box 1 (−75) or its downstream E2 box 3 (−25), or in both E2 boxes was performed [...]."[3]

Wild-type "SIP1 represses the E-cadherin promoter, likely through binding via both zinc finger clusters to spaced E2 boxes as demonstrated previously (Remacle et al., 1999) and confirmed here by a DNA-mediated pull-down assay of SIP1 protein [...]. Wild-type but not mutated SIP1 from transfected human cells could be efficiently precipitated by biotinylated E-cadherin promoter oligonucleotides, comprising two wild-type E2 box sequences. Mutation of the E2 boxes resulted in the loss of SIP1 binding."[3]

Human E2 boxes are E2-box 1 (GCAGGTGA), E2-box 2 (TGGCCGGC) and E2-box 3 (TCACCTGG).[3]

"Alignment of the E-cadherin promoter sequences of dog, mouse, and man. Conserved regulatory elements are indicated: E2 boxes 1 and 3, CCAAT box, and GC box. The E2 box 2 has been described as part of a palindromic E-pal sequence in the mouse E-cadherin promoter (Behrens et al., 1991), but is conserved neither in canine nor in human sequences."[3]

Snails

"Snail family genes encode zinc finger-containing proteins that function primarily as transcriptional repressors [1,2]. To date, three members of the Snail gene family have been described in vertebrates: Snai1 (also known as Snail), Snai2 (Slug) and Snai3 (Smuc). Snail family proteins possess a highly conserved carboxy-terminal region, containing four or five Cys2-His2 (C2H2)-type zinc finger regions and a more divergent amino-terminus that contains the evolutionarily conserved SNAG domain. The zinc finger regions are sequence-specific DNA-binding domains that bind E2-box sequences (CAGGTG and CACCTG). Both the SNAI1 and SNAI2 proteins recruit other proteins, such as histone deacetylase-1 (HDAC-1), to the E2 boxes of target genes to form a transcriptional repression complex that suppresses the transcription of Snail target genes [3,4]."[4]

"We searched the regions from −2500 bp to +500 bp of the Snai1 and Snai2 genes for E2 box sequences (CACCTG and CAGGTG), and identified eleven in the Snai1 promoter region [...] and five in the Snai2 promoter region [...]."[4]

"ChIP assays demonstrated binding of the SNAI1 and SNAI2 proteins to a subset of E2 boxes in both their own and each other’s promoter regulatory regions [...]. The SNAI2 protein bound to the Snai1 promoter region at sites 4, 7 and 8 [...], whereas the SNAI1 protein bound to its own promoter region at sites 2, 3, 4, 7, and 8 [...]. Conversely, the SNAI1 protein bound to the Snai2 promoter region at site 5 [...], whereas the SNAI2 protein bound its own promoter region at site 3, 4 and 5 [...]."[4]

E2 box samplings

  1. Negative strand, negative direction: 5, ACAGATGT at 4213, ACAGATGT at 2989, GCAGTTGG at 1514, ACAGATGT at 1225, ACAGATGT at 48.
  2. Negative strand, positive direction: (G/A)CAG(A/C/G/T)TG(A/C/G/T): 1, GCAGATGA at 37.
  3. Positive strand, negative direction: 2, ACAGATGA at 3920, GCAGGTGG at 2571.
  4. Positive strand, positive direction: 0.
  5. inverse complement, negative strand, negative direction: (A/C/G/T)CA(A/C/G/T)CTG(C/T): 1, CCACCTGT at 2117.
  6. inverse complement, negative strand, positive direction: 0.
  7. inverse complement, positive strand, negative direction: 4, CCACCTGT at 394, ACACCTGT at 1131, GCAACTGC at 3851, ACACCTGT at 3970.
  8. inverse complement, positive strand, positive direction: 0.

E2box (4560-2846) UTRs

  1. Negative strand, negative direction: ACAGATGT at 4213, ACAGATGT at 2989.
  2. Positive strand, negative direction: ACACCTGT at 3970, ACAGATGA at 3920, GCAACTGC at 3851.

E2box negative direction (2596-1) distal promoters

  1. Negative strand, negative direction: CCACCTGT at 2117, GCAGTTGG at 1514, ACAGATGT at 1225, ACAGATGT at 48.
  2. Positive strand, negative direction: GCAGGTGG at 2571, ACACCTGT at 1131, CCACCTGT at 394.

E2box positive direction (4050-1) distal promoters

  1. Negative strand, positive direction: GCAGATGA at 37.

E2 box random dataset samplings

  1. E2boxr0: 2, GCAGTTGC at 3441, ACAGGTGC at 3399.
  2. E2boxr1: 1, ACAGTTGC at 3389.
  3. E2boxr2: 3, ACAGTTGG at 4537, GCAGTTGG at 3246, ACAGATGA at 1827.
  4. E2boxr3: 1, GCAGGTGC at 2881.
  5. E2boxr4: 1, ACAGATGG at 4203.
  6. E2boxr5: 2, GCAGGTGG at 2214, ACAGGTGC at 698.
  7. E2boxr6: 2, GCAGGTGC at 3801, GCAGTTGA at 3330.
  8. E2boxr7: 0.
  9. E2boxr8: 1, GCAGTTGG at 2301.
  10. E2boxr9: 0.
  11. E2boxr0ci: 2, TCAACTGT at 3468, CCACCTGC at 1000.
  12. E2boxr1ci: 2, ACAACTGT at 2753, ACATCTGC at 1132.
  13. E2boxr2ci: 2, CCAGCTGT at 4213, TCATCTGC at 204.
  14. E2boxr3ci: 1, ACATCTGC at 3287.
  15. E2boxr4ci: 2, ACACCTGT at 1959, TCACCTGC at 1914.
  16. E2boxr5ci: 1, TCAGCTGC at 2163.
  17. E2boxr6ci: 3, TCACCTGT at 4359, CCAACTGC at 3822, CCAGCTGT at 2882.
  18. E2boxr7ci: 1, TCAACTGT at 21.
  19. E2boxr8ci: 2, CCAACTGC at 3659, CCATCTGT at 1712.
  20. E2boxr9ci: 2, GCACCTGT at 1899, ACAACTGC at 122.

E2boxr arbitrary (evens) (4560-2846) UTRs

  1. E2boxr0: GCAGTTGC at 3441, ACAGGTGC at 3399.
  2. E2boxr2: ACAGTTGG at 4537, GCAGTTGG at 3246.
  3. E2boxr4: ACAGATGG at 4203.
  4. E2boxr6: GCAGGTGC at 3801, GCAGTTGA at 3330.
  5. E2boxr0ci: TCAACTGT at 3468.
  6. E2boxr2ci: CCAGCTGT at 4213.
  7. E2boxr6ci: TCACCTGT at 4359, CCAACTGC at 3822, CCAGCTGT at 2882.
  8. E2boxr8ci: CCAACTGC at 3659.

E2boxr alternate (odds) (4560-2846) UTRs

  1. E2boxr1: ACAGTTGC at 3389.
  2. E2boxr3: GCAGGTGC at 2881.
  3. E2boxr3ci: ACATCTGC at 3287.

E2boxr alternate positive direction (evens) (4445-4265) core promoters

  1. E2boxr6ci: TCACCTGT at 4359.

E2boxr alternate negative direction (odds) (2811-2596) proximal promoters

  1. E2boxr1ci: ACAACTGT at 2753.

E2boxr alternate positive direction (evens) (4265-4050) proximal promoters

  1. E2boxr4: ACAGATGG at 4203.
  2. E2boxr2ci: CCAGCTGT at 4213.

E2boxr arbitrary negative direction (evens) (2596-1) distal promoters

  1. E2boxr2: ACAGATGA at 1827.
  2. E2boxr8: GCAGTTGG at 2301.
  3. E2boxr0ci: CCACCTGC at 1000.
  4. E2boxr2ci: TCATCTGC at 204.
  5. E2boxr4ci: ACACCTGT at 1959, TCACCTGC at 1914.
  6. E2boxr8ci: CCATCTGT at 1712.

E2boxr alternate negative direction (odds) (2596-1) distal promoters

  1. E2boxr5: GCAGGTGG at 2214, ACAGGTGC at 698.
  2. E2boxr1ci: ACATCTGC at 1132.
  3. E2boxr5ci: TCAGCTGC at 2163.
  4. E2boxr7ci: TCAACTGT at 21.
  5. E2boxr9ci: GCACCTGT at 1899, ACAACTGC at 122.

E2boxr arbitrary positive direction (odds) (4050-1) distal promoters

  1. E2boxr1: ACAGTTGC at 3389.
  2. E2boxr3: GCAGGTGC at 2881.
  3. E2boxr5: GCAGGTGG at 2214, ACAGGTGC at 698.
  4. E2boxr1ci: ACAACTGT at 2753, ACATCTGC at 1132.
  5. E2boxr3ci: ACATCTGC at 3287.
  6. E2boxr5ci: TCAGCTGC at 2163.
  7. E2boxr7ci: TCAACTGT at 21.
  8. E2boxr9ci: GCACCTGT at 1899, ACAACTGC at 122.

E2boxr alternate positive direction (evens) (4050-1) distal promoters

  1. E2boxr0: GCAGTTGC at 3441, ACAGGTGC at 3399.
  2. E2boxr2: GCAGTTGG at 3246, ACAGATGA at 1827.
  3. E2boxr6: GCAGGTGC at 3801, GCAGTTGA at 3330.
  4. E2boxr8: GCAGTTGG at 2301.
  5. E2boxr0ci: TCAACTGT at 3468, CCACCTGC at 1000.
  6. E2boxr2ci: TCATCTGC at 204.
  7. E2boxr4ci: ACACCTGT at 1959, TCACCTGC at 1914.
  8. E2boxr6ci: CCAACTGC at 3822, CCAGCTGT at 2882.
  9. E2boxr8ci: CCAACTGC at 3659, CCATCTGT at 1712.

E2 box analysis and results

Main article: Complex locus A1BG and ZNF497 § E2 boxes

"The most dramatic impact on immunoglobulin gene enhancer activity was observed upon mutation of sites that contain an E2-box motif (G/ACAGNTGN)."[1]

Reals or randoms Promoters direction Numbers Strands Occurrences Averages (± 0.1)
Reals UTR negative 5 2 2.5 2.5 ± 0.5 (--2,+-3)
Randoms UTR arbitrary negative 13 10 1.3 0.8
Randoms UTR alternate negative 3 10 0.3 0.8
Reals Core negative 0 2 0 0
Randoms Core arbitrary negative 0 10 0 0
Randoms Core alternate negative 0 10 0 0
Reals Core positive 0 2 0 0
Randoms Core arbitrary positive 0 10 0 0.05
Randoms Core alternate positive 1 10 0.1 0.05
Reals Proximal negative 0 2 0 0
Randoms Proximal arbitrary negative 0 10 0 0.05
Randoms Proximal alternate negative 1 10 0.1 0.05
Reals Proximal positive 0 2 0 0
Randoms Proximal arbitrary positive 0 10 0 0.1
Randoms Proximal alternate positive 2 10 0.2 0.1
Reals Distal negative 7 2 3.5 3.5 ± 0.5 (--4,+-3)
Randoms Distal arbitrary negative 7 10 0.7 0.7
Randoms Distal alternate negative 7 10 0.7 0.7
Reals Distal positive 1 2 0.5 0.5
Randoms Distal arbitrary positive 11 10 1.1 1.35
Randoms Distal alternate positive 16 10 1.6 1.35

Comparison:

The occurrences of real E2 box UTRs and the negative direction distals are greater than the randoms, the positive direction distals are lower than for the randoms. This suggests that the real E2 boxes are likely active or activable.

Acknowledgements

The content on this page was first contributed by: Henry A. Hoff.

Initial content for this page in some instances came from Wikiversity.

See also

References

  1. ↑ 1.0 1.1 Cornelis Murre and David Baltimore (1992). "The Helix-Loop-Helix Motif: Structure and Function, In: Transcriptional Regulation". 22B. Cold Spring Harbor Laboratory Press: 861–79. doi:10.1101/087969425.22B.861. Retrieved 2017-02-08.
  2. ↑ Cornelis Murre, Gretchen Bain, Marc A. van Dijk, Isaac Engel, Beth A. Furnari, Mark E. Massari, James R. Matthews, Melanie W. Quong, Richard R. Rivera, Maarten H. Stuiver (June 1994). "Structure and function of helix-loop-helix proteins". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1218 (2): 129–35. Retrieved 2017-02-08.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Joke Comijn, Geert Berx, Petra Vermassen, Kristin Verschueren, Leo van Grunsven, Erik Bruyneel, Marc Mareel, Danny Huylebroeck, Frans van Roy (June 2001). "The Two-Handed E Box Binding Zinc Finger Protein SIP1 Downregulates E-Cadherin and Induces Invasion". Molecular Cell. 7 (6): 1267–78. doi:10.1016/S1097-2765(01)00260-X. Retrieved 11 January 2019.
  4. ↑ 4.0 4.1 4.2 Ying Chen and Thomas Gridley (June 7, 2013). "The Snai1 and Snai2 proteins occupy their own and each other's promoter during chondrogenesis". Biochem Biophys Res Commun. 435 (3): 356–360. doi:10.1016/j.bbrc.2013.04.086. Retrieved 12 January 2019.

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