MEF-2 function is modified by a novel co-repressor, MITR

The MEF-2 proteins are a family of transcriptional activators that have bee n detected in a wide variety of cell types. In skeletal muscle cells, MEF-2 proteins interact with members of the MyoD family of transcriptional activ ators to synergistically activate gene expression. Similar interactions wit h 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 tra nscriptionally inactive mutant of Xenopus MEF2D in a yeast two-hybrid scree n. This approach has identified a novel protein expressed in the early embr yo that binds to XMEF2D and XMEF2A. The MEF-2 interacting transcription rep ressor (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 resp onse factor. In the early embryo, MITR expression commences at the neurula stage within the mature somites and is subsequently restricted to the myoto mal muscle. In functional assays, MITR negatively regulates MEF-2-dependent transcription and we show that this repression is mediated by direct bindi ng of MITR to the histone deacetylase HDAC1, Thus, we propose that MITR act s as a co-repressor, recruiting a specific deacetylase to downregulate MEF- 2 activity.