mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity

Recently we identified a new family of histone deacetylases in higher eukar yotes related to yeast HDA1 and showed their differentiation-dependent expr ession. Data presented here indicate that HDAC5 (previously named mHDA1), o ne member of this family, might be a potent regulator of cell differentiati on by interacting specifically with determinant transcription factors. We f ound that HDAC5 was able to interact in vivo and in vitro with MEF2A a MADS box transcription factor, and to strongly inhibit its transcriptional acti vity. Surprisingly, this repression was independent of HDAC5 deacetylase do main. The N-terminal non-deacetylase domain of HDAC5 was able to ensure an efficient repression of MEF2A-dependent transcription. We then mapped prote in domains involved in the HDAC5-MEF2A interaction and showed that MADS box /MEF2-domain region of MEF2A interacts specifically with a limited region i n the N-terminal part of HDAC5 which also possesses a distinct repressor do main. These data show that two independent class II histone deacetylases HD AC4 and HDAC5 are able to interact with members of the MEF2 transcription f actor family and regulate their transcriptional activity, thus suggesting a critical role for these deacetylases in the control of cell proliferation/ differentiation.