MEF-2 function is modified by a novel co-repressor, MITR.
The MEF-2 proteins are a family of transcriptional activators that have been detected in a wide variety of cell types. In skeletal muscle cells, MEF-2 proteins interact with members of the MyoD family of transcriptional activators to synergistically activate gene expression. Similar interactions with tissue or lineage-specific cofactors may also underlie MEF-2 function in other cell types. In order to screen for such cofactors, we have used a transcriptionally inactive mutant of Xenopus MEF2D in a yeast two-hybrid screen. This approach has identified a novel protein expressed in the early embryo that binds to XMEF2D and XMEF2A. The MEF-2 interacting transcription repressor (MITR) protein binds to the N-terminal MADS/MEF-2 region of the MEF-2 proteins but does not bind to the related Xenopus MADS protein serum response factor. In the early embryo, MITR expression commences at the neurula stage within the mature somites and is subsequently restricted to the myotomal muscle. In functional assays, MITR negatively regulates MEF-2-dependent transcription and we show that this repression is mediated by direct binding of MITR to the histone deacetylase HDAC1. Thus, we propose that MITR acts as a co-repressor, recruiting a specific deacetylase to downregulate MEF-2 activity.
Sparrow
D B
DB
Division of Developmental Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA.
Miska
E A
EA
Langley
E
E
Reynaud-Deonauth
S
S
Kotecha
S
S
Towers
N
N
Spohr
G
G
Kouzarides
T
T
Mohun
T J
TJ
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics / Q000302:isolation & purification; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000196:embryology / Q000378:metabolism; D009154:Mutation; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D014981:Xenopus / Q000196:embryology / Q000235:genetics; D029867:Xenopus Proteins
D002352:Carrier Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D029867:Xenopus Proteins; C486544:HDAC9 protein, human; D006655:Histone Deacetylases; C122050:hdac9-A protein, Xenopus