Epigenetic synergies between methylation of cytosines and biotinylation of histones in gene repression

Folate‐dependent methylation of cytosines is catalyzed by DNA methyltransferases (DNMTs) 1, 3a, and 3b; its role in gene repression is mediated by methyl‐CpG‐binding protein 2 (MeCP2). The binding of biotin to histones H3 and H4 is catalyzed by holocarboxylase synthetase (HCS) and also causes gene repression. Cytosine methylation marks and histone biotinylation marks co‐localize in long‐terminal repeats (LTRs). HCS lacks a DNA‐binding domain and it is unknown how HCS is guided to its target loci in chromatin. We hypothesized that cytosine methylation is essential for the chromatin binding of HCS and subsequent histone biotinylation. When cytosine methylation marks at LTR22 were erased by treatment with azacytidine, enrichment of H4K12bio at the same locus decreased by ~50%, while HCS knockdown did not affect cytosine methylation. These observations are consistent with our hypothesis. We are currently studying the physical interactions among HCS, DNMTs, and MeCP2 by using Y2H assays, Co‐IP assays and limited proteolysis assays to provide a mechanistic explanation for the enrichment of biotinylated histones at cytosine methylation sites. This is the first report on epigenetic synergies between cytosine methylation and histone biotinylation. Grant Funding Source : UNL ARD, NIH grants DK063945, DK077816, DK082476 and ES015206