Gene Symbol: Tcf12
Description: transcription factor 12
Alias: A130037E08Rik, ALF1, HEB, HEBAlt, HTF-4, HTF4, ME1, REB, bHLHb20, transcription factor 12, DNA-binding protein HTF4, E-box-binding protein, TCF-12, class A helix-loop-helix transcription factor ME1, transcription factor HTF-4
Species: mouse
Products:     Tcf12

Top Publications

  1. Murakami M, Kataoka K, Tominaga J, Nakagawa O, Kurihara H. Differential cooperation between dHAND and three different E-proteins. Biochem Biophys Res Commun. 2004;323:168-74 pubmed bait, which led to identification of several dHAND-binding proteins, including three E-proteins: E2A, ME2, and ALF1. Subsequent analysis revealed that although their heterodimerization and transcriptional activities were similar, ..
  2. In T, Trotman Grant A, Fahl S, Chen E, Zarin P, Moore A, et al. HEB is required for the specification of fetal IL-17-producing ?? T cells. Nat Commun. 2017;8:2004 pubmed publisher
    ..Here we show that HEB (HeLa E-box binding protein, encoded by Tcf12) is required for the generation of a newly defined subset of fetal-derived CD73- ??T17 cells...
  3. Neuman T, Keen A, Knapik E, Shain D, Ross M, Nornes H, et al. ME1 and GE1: basic helix-loop-helix transcription factors expressed at high levels in the developing nervous system and in morphogenetically active regions. Eur J Neurosci. 1993;5:311-8 pubmed
    ..The cloned cDNAs (ME1, ME2, ME3, ME4, in the mouse and GE1, GE2 in the chick) have HLH coding regions highly homologous to other known ..
  4. Barndt R, Dai M, Zhuang Y. A novel role for HEB downstream or parallel to the pre-TCR signaling pathway during alpha beta thymopoiesis. J Immunol. 1999;163:3331-43 pubmed
    ..How the pre-TCR signal leads to downstream gene expression is not known. HeLa E-box binding protein (HEB), a basic helix-loop-helix transcription factor, is abundantly detected in thymocytes and is thought to regulate E-..
  5. Stewart H, Zoidl G, Rossner M, Brennan A, Zoidl C, Nave K, et al. Helix-loop-helix proteins in Schwann cells: a study of regulation and subcellular localization of Ids, REB, and E12/47 during embryonic and postnatal development. J Neurosci Res. 1997;50:684-701 pubmed
    ..In this study, we have analyzed the expression of the dominant negative HLH genes, Id1 to Id4 and the class A gene REB, during Schwann cell development...
  6. Parker M, Perry R, Fauteux M, Berkes C, Rudnicki M. MyoD synergizes with the E-protein HEB beta to induce myogenic differentiation. Mol Cell Biol. 2006;26:5771-83 pubmed
    ..The E-protein HEB is alternatively spliced to generate alpha and beta isoforms...
  7. Tanigawa Y, Yakura R, Komiya T. The bHLH transcription factor Tcf12 (ME1) mRNA is abundantly expressed in Paneth cells of mouse intestine. Gene Expr Patterns. 2007;7:709-13 pubmed
    Using a large-scale in situ hybridization screening system, we found that mRNA coding for ME1, a basic helix-loop-helix (bHLH) transcription factor, was abundantly expressed in Paneth cells of adult small intestinal crypts...
  8. Welinder E, Mansson R, Mercer E, Bryder D, Sigvardsson M, Murre C. The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor. Proc Natl Acad Sci U S A. 2011;108:17402-7 pubmed publisher
    ..Here, we show that lymphocyte development in HEB-ablated mice exhibits a partial developmental arrest, whereas B-cell development in E2A(+/-)HEB(-/-) mice is ..
  9. Zhuang Y, Cheng P, Weintraub H. B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB. Mol Cell Biol. 1996;16:2898-905 pubmed
    ..In this study, the control mechanism of E2A was further explored by disruption of the E2A-related genes, E2-2 and HEB. In contrast to E2A, E2-2 and HEB are not essential for the establishment of the B-cell lineage...

More Information


  1. D Cruz L, Lind K, Wu B, Fujimoto J, Goldrath A. Loss of E protein transcription factors E2A and HEB delays memory-precursor formation during the CD8+ T-cell immune response. Eur J Immunol. 2012;42:2031-41 pubmed publisher
    The transcription factors E2A and HEB (members of the E protein family) have been shown to play essential roles in lymphocyte development, while their negative regulators, the Id proteins, have been implicated in both lymphocyte ..
  2. Sharma V, Fenwick A, Brockop M, McGowan S, Goos J, Hoogeboom A, et al. Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. Nat Genet. 2013;45:304-7 pubmed publisher
    ..Using exome sequencing, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis...
  3. Li J, Wu D, Jiang N, Zhuang Y. Combined deletion of Id2 and Id3 genes reveals multiple roles for E proteins in invariant NKT cell development and expansion. J Immunol. 2013;191:5052-64 pubmed publisher
    ..Collectively, these findings suggest that Id2- and Id3-mediated inhibition of E proteins controls iNKT development by restricting lineage choice and population expansion. ..
  4. Wikström I, Forssell J, Goncalves M, Colucci F, Holmberg D. E2-2 regulates the expansion of pro-B cells and follicular versus marginal zone decisions. J Immunol. 2006;177:6723-9 pubmed
    ..Although E2A mRNA showed a similar tendency, the difference was not significant. Collectively, our findings indicate that E2-2 is required for optimal expansion of pro-B cells, and also influences the follicular vs MZ decision. ..
  5. Yoon S, Foley J, Baker J. HEB associates with PRC2 and SMAD2/3 to regulate developmental fates. Nat Commun. 2015;6:6546 pubmed publisher
    ..We demonstrate that the helix-loop-helix (HLH) protein, HEB, directly associates with the Polycomb repressive complex 2 (PRC2) at a subset of developmental promoters, ..
  6. Tremblay M, Herblot S, Lecuyer E, Hoang T. Regulation of pT alpha gene expression by a dosage of E2A, HEB, and SCL. J Biol Chem. 2003;278:12680-7 pubmed
    ..We have shown that the transcription factors E2A and HEB associate with high affinity to these E-boxes...
  7. Chen Y, Yang C, Kao S, Liu C, Lin S, Chang K. MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity. Cancer Res. 2016;76:4872-86 pubmed publisher
    ..In silico and experimental evidence further revealed that miR-211 directly targeted transcription factor 12 (TCF12), which mediated suppressor activities in OSCC cells and was drastically downregulated in tumor ..
  8. Hjelmsoe I, Allen C, Cohn M, Tulchinsky E, Wu L. The kappaB and V(D)J recombination signal sequence binding protein KRC regulates transcription of the mouse metastasis-associated gene S100A4/mts1. J Biol Chem. 2000;275:913-20 pubmed
    ..Two clones corresponding to the DNA-binding proteins KRC and Alf1 were identified...
  9. Mulligan M, Ponomarev I, Hitzemann R, Belknap J, Tabakoff B, Harris R, et al. Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis. Proc Natl Acad Sci U S A. 2006;103:6368-73 pubmed
    ..9 were identified: Arhgef12, Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d, Scn4b, Tcf12, Vps11, and Zfp291 and four ESTs...
  10. Yamazaki K, Mizui Y, Sagane K, Tanaka I. Assignment of a disintegrin and metalloproteinase domain 10 (Adam10) gene to mouse chromosome 9. Genomics. 1997;46:528-9 pubmed
  11. Uittenbogaard M, Chiaramello A. Expression of the basic Helix-Loop-Helix ME1 E-protein during development and aging of the murine cerebellum. Neurosci Lett. 1999;274:191-4 pubmed
    ..mechanisms of bHLH proteins orchestrating cerebellar development, we explored the spatio-temporal expression of the ME1 E-protein...
  12. Gradwohl G, Fode C, Guillemot F. Restricted expression of a novel murine atonal-related bHLH protein in undifferentiated neural precursors. Dev Biol. 1996;180:227-41 pubmed
    ..Its structure and expression pattern suggest that MATH4A may regulate an early step of neural development, either as a partner of ubiquitous bHLH proteins or associated with other neural-specific bHLH proteins. ..
  13. Jones M, Zhuang Y. Acquisition of a functional T cell receptor during T lymphocyte development is enforced by HEB and E2A transcription factors. Immunity. 2007;27:860-70 pubmed
    ..We have shown here that the structurally and functionally related transcription factors HEB and E2A work together to maintain DP fate and to control the DP to SP transition...
  14. D Cruz L, Stradner M, Yang C, Goldrath A. E and Id proteins influence invariant NKT cell sublineage differentiation and proliferation. J Immunol. 2014;192:2227-36 pubmed publisher
    ..Thus, we provide insight into E and Id protein regulation of iNKT cell proliferation and differentiation to specific sublineages during development in the thymus. ..
  15. Braunstein M, Rajkumar P, Claus C, Vaccarelli G, Moore A, Wang D, et al. HEBAlt enhances the T-cell potential of fetal myeloid-biased precursors. Int Immunol. 2010;22:963-72 pubmed publisher
    ..We have found that the transcription factor HEBAlt is up-regulated in early hematopoietic precursors in response to DL-Notch signaling and that it can promote early ..
  16. Wang D, Claus C, Rajkumar P, Braunstein M, Moore A, Sigvardsson M, et al. Context-dependent regulation of hematopoietic lineage choice by HEBAlt. J Immunol. 2010;185:4109-17 pubmed publisher
    ..We found that a short form of HEB, HEBAlt, acts downstream of Delta-like (DL)-Notch signaling to promote T cell development...
  17. Lazorchak A, Wojciechowski J, Dai M, Zhuang Y. E2A promotes the survival of precursor and mature B lymphocytes. J Immunol. 2006;177:2495-504 pubmed
    ..ectopic expression of Id proteins, which inhibit E2A as well as other basic helix-loop-helix proteins such as HEB, suggest additional roles of E2A at later stages of B cell development...
  18. Dear T, Hainzl T, Follo M, Nehls M, Wilmore H, Matena K, et al. Identification of interaction partners for the basic-helix-loop-helix protein E47. Oncogene. 1997;14:891-8 pubmed
    ..A cDNA encoding part of the nucleolin protein sequence interacted with the E47 basic-helix-loop-helix only when fused to a beta-galactosidase tag. ..
  19. Popova N, Morris R. Genetic regulation of mouse stem cells: identification of two keratinocyte stem cell regulatory loci. Curr Top Microbiol Immunol. 2004;280:111-37 pubmed
  20. Vernes S, Oliver P, Spiteri E, Lockstone H, Puliyadi R, Taylor J, et al. Foxp2 regulates gene networks implicated in neurite outgrowth in the developing brain. PLoS Genet. 2011;7:e1002145 pubmed publisher
    ..Our data indicate that Foxp2 modulates neuronal network formation, by directly and indirectly regulating mRNAs involved in the development and plasticity of neuronal connections. ..
  21. CISSE B, Caton M, Lehner M, Maeda T, Scheu S, Locksley R, et al. Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell. 2008;135:37-48 pubmed publisher
    ..These results identify E2-2 as a specific transcriptional regulator of the PDC lineage in mice and humans and reveal a key function of E proteins in the innate immune system. ..
  22. Zhang B, Lin Y, Dai M, Zhuang Y. Id3 and Id2 act as a dual safety mechanism in regulating the development and population size of innate-like ?? T cells. J Immunol. 2014;192:1055-1063 pubmed publisher
    ..1(+)V?6.3(+) T cell expansion in Id2 and Id3 double conditional knockout mice. Our data indicated that Id2 and Id3 collaboratively control survival and expansion of the ?? lineage through modulating a proper threshold of E proteins. ..
  23. Pan L, Hanrahan J, Li J, Hale L, Zhuang Y. An analysis of T cell intrinsic roles of E2A by conditional gene disruption in the thymus. J Immunol. 2002;168:3923-32 pubmed
    ..In contrast to germline E2A knockout mice, conditional E2A knockout mice do not develop T cell lymphoma. This work establishes a new model for further investigating E2A function in T cell development and leukemiogenesis. ..
  24. Zhuang Y, Soriano P, Weintraub H. The helix-loop-helix gene E2A is required for B cell formation. Cell. 1994;79:875-84 pubmed
    ..Surprisingly, heterozygous embryos contain, on average, about half as many B cells as wild-type embryos, suggesting the existence of a counting mechanism that translates levels of E2A into numbers of B cells. ..
  25. Flora A, Garcia J, Thaller C, Zoghbi H. The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors. Proc Natl Acad Sci U S A. 2007;104:15382-7 pubmed
  26. Krapp A, Knöfler M, Frutiger S, Hughes G, Hagenbuchle O, Wellauer P. The p48 DNA-binding subunit of transcription factor PTF1 is a new exocrine pancreas-specific basic helix-loop-helix protein. EMBO J. 1996;15:4317-29 pubmed
    ..Thus the pancreas-specific DNA-binding activity of PTF1 originates from the synthesis of at least one cell-specific component rather than from a cell-specific assembly of more widely distributed proteins. ..
  27. Wojciechowski J, Lai A, Kondo M, Zhuang Y. E2A and HEB are required to block thymocyte proliferation prior to pre-TCR expression. J Immunol. 2007;178:5717-26 pubmed
    ..E2A and HEB are structurally and functionally related basic helix-loop-helix transcription factors involved in T cell ..
  28. Yoshida S, Ohbo K, Takakura A, Takebayashi H, Okada T, Abe K, et al. Sgn1, a basic helix-loop-helix transcription factor delineates the salivary gland duct cell lineage in mice. Dev Biol. 2001;240:517-30 pubmed
    ..In addition, Sgn1 expression exhibits a reverse relationship with the development of male phenotypes, suggesting its role in gender dimorphism in the salivary glands. ..
  29. Braunstein M, Anderson M. HEB-deficient T-cell precursors lose T-cell potential and adopt an alternative pathway of differentiation. Mol Cell Biol. 2011;31:971-82 pubmed publisher
    ..Previously, we discovered that the E-protein transcription factor HEBAlt promoted T-cell specification...
  30. Wikström I, Forssell J, Penha Goncalves M, Bergqvist I, Holmberg D. A role for E2-2 at the DN3 stage of early thymopoiesis. Mol Immunol. 2008;45:3302-11 pubmed publisher
    Roles for the E-proteins E2A and HEB during T lymphocyte development have been well established...
  31. Jones Mason M, Zhao X, Kappes D, Lasorella A, Iavarone A, Zhuang Y. E protein transcription factors are required for the development of CD4(+) lineage T cells. Immunity. 2012;36:348-61 pubmed publisher
    ..SP) transition during T cell development is initiated by downregulation of the E protein transcription factors HEB and E2A...
  32. Loveys D, Streiff M, Kato G. E2A basic-helix-loop-helix transcription factors are negatively regulated by serum growth factors and by the Id3 protein. Nucleic Acids Res. 1996;24:2813-20 pubmed
    ..Four murine cDNAs were identified in the screen, all of which encode helix-loop-helix proteins: E12, E47, ALF1 and Id4...
  33. Soosaar A, Chiaramello A, Zuber M, Neuman T. Expression of basic-helix-loop-helix transcription factor ME2 during brain development and in the regions of neuronal plasticity in the adult brain. Brain Res Mol Brain Res. 1994;25:176-80 pubmed
    ..The specific expression of ME2 during development and in the regions of neuronal plasticity in the adult brain suggest that ME2 may have a regulatory function in developmental processes as well as during neuronal plasticity. ..
  34. Nielsen A, Pallisgaard N, Pedersen F, Jørgensen P. Murine helix-loop-helix transcriptional activator proteins binding to the E-box motif of the Akv murine leukemia virus enhancer identified by cDNA cloning. Mol Cell Biol. 1992;12:3449-59 pubmed
    ..We have identified seven lambda clones expressing DNA-binding proteins representing two different genes termed ALF1 and ALF2...
  35. Nef S, Schaad O, Stallings N, Cederroth C, Pitetti J, Schaer G, et al. Gene expression during sex determination reveals a robust female genetic program at the onset of ovarian development. Dev Biol. 2005;287:361-77 pubmed
    ..These studies define the major characteristics of testicular and ovarian transcriptional programs and reveal the richness of signaling processes in differentiation of the bipotential gonads into testes and ovaries. ..
  36. Hollenberg S, Sternglanz R, Cheng P, Weintraub H. Identification of a new family of tissue-specific basic helix-loop-helix proteins with a two-hybrid system. Mol Cell Biol. 1995;15:3813-22 pubmed
    ..Transient transfection of NIH 3T3 cells with GAL4-Th1 fusions reveals a repression activity mediated by the Th1 bHLH domain. In combination, these properties define Th1 as a new bHLH protein with a unique set of properties. ..
  37. D Cruz L, Knell J, Fujimoto J, Goldrath A. An essential role for the transcription factor HEB in thymocyte survival, Tcra rearrangement and the development of natural killer T cells. Nat Immunol. 2010;11:240-9 pubmed publisher
    ..Contrary to that, we report here that the E protein HEB was uniquely required at the CD4(+)CD8(+) double-positive (DP) stage of T cell development...
  38. Zhang H, Hsu H, Yang P, Yang X, Wu Q, Liu Z, et al. Identification of multiple genetic loci that regulate adenovirus gene therapy. Gene Ther. 2004;11:4-14 pubmed
    ..0 cM) and Chr 8 (52 and 73.0 cM). These results indicate that different strains of mice exhibit different pathways for effective clearance of AdLacZ depending on genetic polymorphisms and interactions at multiple genetic loci. ..
  39. Braunstein M, Anderson M. Developmental progression of fetal HEB(-/-) precursors to the pre-T-cell stage is restored by HEBAlt. Eur J Immunol. 2010;40:3173-82 pubmed publisher
    ..We have identified a unique form of HEB, called HEBAlt, which is expressed only during the early stages of T-cell development, whereas HEBCan is expressed throughout T-..
  40. Rose S, Swift G, Peyton M, Hammer R, MacDonald R. The role of PTF1-P48 in pancreatic acinar gene expression. J Biol Chem. 2001;276:44018-26 pubmed
    ..We show that the acinar cell-specific bHLH protein PTF1-P48 and the common bHLH cofactor HEB are part of the PTF1 complex that binds the A element and mediates its activity...
  41. Nielsen A, Clark M, Taylor B, Jorgensen P, Hjorth J. ALF1, a basic helix-loop-helix transcription factor, maps to mouse chromosome 9. Mamm Genome. 1996;7:244 pubmed
  42. Yi S, Yu M, Yang S, Miron R, Zhang Y. Tcf12, A Member of Basic Helix-Loop-Helix Transcription Factors, Mediates Bone Marrow Mesenchymal Stem Cell Osteogenic Differentiation In Vitro and In Vivo. Stem Cells. 2017;35:386-397 pubmed publisher
    ..In the present study, Tcf12 was investigated for its involvement in the osteoblastic cell commitment of MSCs...
  43. Sun X, Copeland N, Jenkins N, Baltimore D. Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins. Mol Cell Biol. 1991;11:5603-11 pubmed
    ..E47 and E2B.m3, but not that of the other set, including TFE3, USF, and AP4. The Id proteins also homodimerize poorly. Expression of both Id genes is down-regulated during differentiation in a variety of cell types. ..
  44. Park S, Chen W, Cierpicki T, Tonelli M, Cai X, Speck N, et al. Structure of the AML1-ETO eTAFH domain-HEB peptide complex and its contribution to AML1-ETO activity. Blood. 2009;113:3558-67 pubmed publisher homologous to several TATA binding protein-associated factors (TAFs) and interacts with E proteins (E2A and HEB)...
  45. Chen B, Lim R. Physical and functional interactions between the transcriptional inhibitors Id3 and ITF-2b. Evidence toward a novel mechanism regulating muscle-specific gene expression. J Biol Chem. 1997;272:2459-63 pubmed
    ..Taken together, this study reveals a more complex pattern of regulatory interactions involving the helix-loop-helix proteins than was previously anticipated. ..
  46. Jia J, Dai M, Zhuang Y. E proteins are required to activate germline transcription of the TCR Vbeta8.2 gene. Eur J Immunol. 2008;38:2806-20 pubmed publisher
    ..2 germline transcription depends more on the E proteins encoded by the E2A gene than by the HEB gene. We further show that IL-7 receptor (IL-7R)-mediated signals are essential for Vbeta8.2 germline transcription...
  47. Ravanpay A, Olson J. E protein dosage influences brain development more than family member identity. J Neurosci Res. 2008;86:1472-81 pubmed publisher, using coimmunoprecipitation in a culture model of neurogenesis (P19 cells), we show that E proteins E12, HEB, and E2-2 interact with neuroD2...
  48. Popova N, Teti K, Wu K, Morris R. Identification of two keratinocyte stem cell regulatory loci implicated in skin carcinogenesis. Carcinogenesis. 2003;24:417-25 pubmed
  49. Wang D, Claus C, Vaccarelli G, Braunstein M, Schmitt T, Zuniga Pflucker J, et al. The basic helix-loop-helix transcription factor HEBAlt is expressed in pro-T cells and enhances the generation of T cell precursors. J Immunol. 2006;177:109-19 pubmed
    ..We have cloned a new transcription factor, called HEBAlt, from a pro-T cell cDNA library...
  50. Zhang Y, Flejter W, Barcroft C, Riviere M, Szpirer J, Szpirer C, et al. Localization of the human HTF4 transcription factors 4 gene (TCF12) to chromosome 15q21. Cytogenet Cell Genet. 1995;68:235-8 pubmed
    ..Toward this goal, we examined a panel of somatic cell hybrids and assigned the gene (TCF12) encoding the helix-loop-helix transcription factors 4 (HTF4) to chromosome 15...
  51. O Neil J, Shank J, Cusson N, Murre C, Kelliher M. TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB. Cancer Cell. 2004;5:587-96 pubmed
    ..To provide genetic evidence that tal1/scl induces leukemia by interfering with E47 and HEB, we expressed tal1/scl in an E2A or HEB heterozygous background...
  52. Williams C, Naito T, Arco P, Seavitt J, Cashman S, De Souza B, et al. The chromatin remodeler Mi-2beta is required for CD4 expression and T cell development. Immunity. 2004;20:719-33 pubmed
    ..Mi-2beta associates with the CD4 enhancer as well as the E box binding protein HEB and the histone acetyltransferase (HAT) p300, enabling their recruitment to the CD4 enhancer and ..
  53. Uittenbogaard M, Chiaramello A. Expression of the bHLH transcription factor Tcf12 (ME1) gene is linked to the expansion of precursor cell populations during neurogenesis. Brain Res Gene Expr Patterns. 2002;1:115-21 pubmed
    In this study, we focused on the potential function of the murine gene Tcf12 (also known as ME1 or HEB) encoding the bHLH E-protein ME1 during brain development...
  54. Li S, Mattar P, Zinyk D, Singh K, Chaturvedi C, Kovach C, et al. GSK3 temporally regulates neurogenin 2 proneural activity in the neocortex. J Neurosci. 2012;32:7791-805 pubmed publisher
    ..We thus conclude that the temporal regulation of Neurog2-E47 heterodimerization by GSK3 is a central component of the neuronal differentiation "clock" that coordinates the timing and tempo of neocortical neurogenesis in mouse. ..
  55. Barndt R, Dai M, Zhuang Y. Functions of E2A-HEB heterodimers in T-cell development revealed by a dominant negative mutation of HEB. Mol Cell Biol. 2000;20:6677-85 pubmed
    ..and differentiation are regulated by the basic helix-loop-helix (bHLH) transcription factors encoded by the E2A and HEB genes...