Abstract

The class II histone deacetylases (HDACs) 4, 5, and 7 share a common structural organization, with a carboxyl-terminal catalytic domain and an amino-terminal extension that mediates interactions with members of the myocyte enhancer factor-2 (MEF2) family of transcription factors. Association of these HDACs with MEF2 factors represses transcription of MEF2 target genes. MEF2-interacting transcription repressor (MITR) shares homology with the amino-terminal extensions of class II HDACs and also acts as a transcriptional repressor, but lacks a histone deacetylase catalytic domain. This suggests that MITR represses transcription by recruiting other corepressors. We show that the amino-terminal regions of MITR and class II HDACs interact with the transcriptional corepressor, COOH-terminal-binding protein (CtBP), through a CtBP-binding motif (P-X-D-L-R) conserved in MITR and HDACs 4, 5, and 7. Mutation of this sequence in MITR abolishes interaction with CtBP and impairs, but does not eliminate, the ability of MITR to inhibit MEF2-dependent transcription. The residual repressive activity of MITR mutants that fail to bind CtBP can be attributed to association with other HDAC family members. These findings reveal CtBP-dependent and -independent mechanisms for transcriptional repression by MITR and show that MITR represses MEF2 activity through recruitment of multicomponent corepressor complexes that include CtBP and HDACs.

Highlights

  • Regulation of chromatin structure is a central mechanism for the control of gene expression and modulation of the acetylation state of nucleosomal histones has been revealed as a dynamic mechanism for chromatin remodeling

  • Sion of basal as well as myocyte enhancer factor-2 (MEF2)-dependent promoters by MEF2-interacting transcription repressor (MITR). These results demonstrate that MITR and class II histone deacetylases (HDACs) act as a bridge linking the COOH-terminalbinding protein (CtBP) corepressor to target transcription factors, such as MEF2, thereby establishing a multiprotein corepressor complex directed at specific downstream genes

  • The results of this study demonstrate that MITR and class II HDACs share homology in an amino-terminal CtBP-binding motif that recruits CtBP to enhance transcriptional repression

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Summary

Introduction

Regulation of chromatin structure is a central mechanism for the control of gene expression and modulation of the acetylation state of nucleosomal histones has been revealed as a dynamic mechanism for chromatin remodeling (reviewed in Ref. 1). MEF2-interacting transcription repressor (MITR) shares homology with the amino-terminal extensions of class II HDACs and acts as a transcriptional repressor, but lacks a histone deacetylase catalytic domain.

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