Distinct Contribution of DNA Methylation and Histone Acetylation to the Genomic Occupancy of Transcription Factors

DNA methylation has been shown to act by directly modulating transcription factor affinity to DNA binding sites and by recruiting methyl-CpG binding proteins, which form complexes with histone deacetylases (HDACs). Both mechanisms can affect gene regulation, but the extent to which HDACs contribute to the function of DNA methylation and transcription factor occupancy is not clear. To address this question we measured gene expression alterations, chromatin accessibility and transcription factor occupancy in wild type or DNA methylation-deficient mouse embryonic stem cells following HDAC inhibition. We observe widespread elevated chromatin accessibility at repeat elements following histone hyper-acetylation, which was magnified by the absence of DNA methylation. Subsets of repeat elements displayed enriched binding by distinct transcription factors and elevated expression. The pronounced additive effect of HDAC inhibition in DNA methylation deficient cells demonstrate that DNA methylation and histone deacetylation act largely independently to supress transcription factor binding and gene expression. Overall design: 126 samples in total. 1) ChIP-seq with exogenous spike-in (16 samples): 8 H3ac ChIP-seq samples including 4 conditions with 2 biological replicates each. 8 input control samples, one for each of the ChIP-seq sample. 2) ATAC-seq experiment (32 samples): 16 ATAC-seq samples including 4 conditions with 4 biological replicates each. 16 control Tn5 tagmented genomic DNA, one for each of the ATAC-seq samples. 3) ChIP-seq (70 samples): 60 ChIP-seq samples: 5 different antibodies with 4 conditions and 3 biological replicates each. 4 Igg control ChIP-seq samples. 6 Input control samples. 4) RNA-seq (8 samples): 4 conditions with 2 biological replicates each.