Different class IIa HDACs repressive complexes regulate specific epigenetic responses related to cell survival in leiomyosarcoma cells.

Purpose: Define the transcriptional networks supervising class IIa HDAC expression. Outcome: We demonstrate that MEF2D is the key factor controlling HDAC9 transcription. Comprehensive genome-wide studies demonstrate that HDAC4 and HDAC9 supervise different genetic programs and show both specific and common genomic bindings. Although the number of MEF2-target genes commonly regulated is similar, only HDAC4 represses many additional genes that are not MEF2D targets. HDAC4-/- and HDAC9-/- cells increase H3K27ac levels around the TSS of the respective repressed genes. However, these genes rarely show bindings of the HDACs at their promoters. Frequently HDAC4 and HDAC9 bind intergenic regions. We demonstrate that these regions, recognized by MEF2D/HDAC4/HDAC9 repressive complexes, show the features of active enhancers. Examination of the H3K27ac histone modification and of MEF2, HDAC4 and HDAC9 binding in SK-UT-1 Leiomyosarcomas cells (WT and HDAC4 or HDAC9 null, mutated using the CRISPR/Cas9 technology).