Enhancer-specific modulation of E protein activity.
Homodimeric complexes of members of the E protein family of basic helix-loop-helix (bHLH) transcription factors are important for tissue-specific activation of genes in B lymphocytes (Bain, G., Gruenwald, S., and Murre, C. (1993) Mol. Cell Biol. 13, 3522-3529; Shen, C. P., and Kadesch, T. (1995) Mol. Cell Biol. 15, 4518-4524; Jacobs, Y., et al. (1994) Mol. Cell Biol. 14, 4087-4096; Wilson, R. B., et al. (1991) Mol. Cell Biol. 11, 6185-6191). These homodimers, however, have little activity on myogenic enhancers (Weintraub, H., Genetta, T., and Kadesch, T. (1994) Genes Dev. 8, 2203-2211). We report here the identification of a novel cis-acting transcriptional repression domain in the E protein family of bHLH transcription factors. This domain, the Rep domain, is present in each of the known vertebrate E proteins. Extensive mapping analysis demonstrates that this domain is an acidic region of 30 amino acids with a predicted loop structure. Fusion studies indicate that the Rep domain can repress both of the E protein transactivation domains (AD1 and AD2). Physiologically, the Rep domain plays a key role in maintaining E protein homodimers in an inactive state on myogenic enhancers. In addition, we demonstrate that Rep domain mediated repression of AD1 is a necessary for the function of MyoD-E protein heterodimeric complexes. These studies demonstrate that the Rep domain is important for modulating the transcriptional activity of E proteins and provide key insights into both the selectivity and mechanism of action of E protein containing bHLH protein complexes.
Markus
Maurice
M
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Du
Zhimei
Z
Benezra
Robert
R
D000595:Amino Acid Sequence; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D004265:DNA Helicases / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D006367:HeLa Cells; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D017565:Sarcoidosis, Pulmonary; D016415:Sequence Alignment; D017384:Sequence Deletion; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D000073940:Transcription Factor 4; D058125:Transcription Factor 7-Like 1 Protein; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D004265:DNA Helicases; D017931:DNA Primers; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D015534:Trans-Activators; D000073940:Transcription Factor 4; D058125:Transcription Factor 7-Like 1 Protein; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; C544912:TCF7L1 protein, human; C544894:TCF7L2 protein, human; C489532:Tcf12 protein, mouse; C075668:Tcf3 protein, mouse; C090743:Tcf4 protein, mouse; C544913:Tcf7l1 protein, mouse; C544895:Tcf7l2 protein, mouse; C045264:replication initiator protein; C073366:TCF12 protein, human