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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
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Homo sapiens
 Snai2
Mus musculus
 PPARA
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Transcription Factor Encyclopedia  BETA
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Overview

The Tcfe2a gene locus is mapped to 10 43.0 cM in mice (Figure 1) and encodes the transcription factor E2A, a member of the “class I” family of basic helix-loop-helix (bHLH) transcription factors (also known simply as “E-proteins”). The bHLH domain is comprised of two amphipathic helicies connected by a flexible loop structure and serves to mediate homo- or heterodimeric interactions with other bHLH domain containing proteins. Other members of the class I family of bHLH proteins in mammals include HEB and E2-2.

The protein products of Tcfe2a, E12 and E47, arise through differential pre-mRNA splicing of the exon encoding both the DNA binding and dimerization domains. The two proteins are highly similar and the differences between the two are essentially limited to the bHLH domain, which features 80% sequence identify (Figure 2). E2A proteins may bind DNA as homo- or heterodimers, depending on the cell context. Heterodimerization partners are tissue-restricted class II bHLH proteins; however, no class II bHLH proteins have been identified in early B-lymphoid progenitors and E2A proteins exist only as homodimers.

Although E2A proteins are expressed in a wide variety of cell types and involved in many biological processes, they are most critical in B-cells. Homozygous Tcfe2a-null mice are devoid of CD19+ B-lymphocytes. Ectopic expression of either E12 or E47 in B-lymphocyte precursors from these mice effectively rescues pro-B lymphocyte development, suggesting that E2A proteins are functionally redundant in this process. E2A proteins are required for critical events in B-cell development including commitment to B-cell lineage, IL-7 mediated expansion of pro-B-lymphocytes, progression to the pre-B-cell stage, Igκ gene rearrangement and IgH chain isotype switching.

E2A proteins control proliferation and differentiation in many cell types. In muscle cells, E2A proteins serve to initiate muscle differentiation through the formation of heterodimers with MyoD [1]. In neurons, E12 forms heterodimers with neuroD2 to induce neurogenesis [2]. In addition to controlling proliferation and differentiation, E2A proteins are also involved in cellular growth suppression through induction of p21WAF/CIP1 [3].

Since E2A proteins are ubiquitously expressed, their activity is tightly controlled by Id proteins, which are natural inhibitors of E-proteins[4][5]. Id proteins are class V bHLH family members that can form heterodimers with E2A proteins. However, Id proteins lack a DNA binding domain and therefore E2A-Id heterodimers are devoid of DNA binding activity, effectively inhibiting E-protein function [5].

References
  1. Sun L et al. E2A protein degradation by the ubiquitin-proteasome system is stage-dependent during muscle differentiation. Oncogene, 26(3):441-8. (PMID 16909127)
  2. Ravanpay AC and Olson JM. E protein dosage influences brain development more than family member identity. J. Neurosci. Res., 86(7):1472-81. (PMID 18214987)
  3. Prabhu S et al. Regulation of the expression of cyclin-dependent kinase inhibitor p21 by E2A and Id proteins. Mol. Cell. Biol., 17(10):5888-96. (PMID 9315646)
  1. Benezra R et al. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell, 61(1):49-59. (PMID 2156629)
  2. Sun XH et al. Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins. Mol. Cell. Biol., 11(11):5603-11. (PMID 1922066)
Figures
FIGURE 1 E2A Domain Structures.
Domain structures of the E2A gene products, E47 and E12. Vertical blue lines in E47 represent non-identical amino acids relative to E12. AD1, activation domain 1; AD2, activation domain 2; bHLH, basic helix-loop-helix.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.