Regulation Of Gene Transcription By Global Promoter DNA Methylation

The precise regulation of gene transcription plays pivotal roles in various biological processes.DNA methylation is one of the most important epigenetic modifications which contributes to the regulation of gene transcription.DNA methylation at promoter regions has long been associated with gene silencing.However,how DNA methylation at promoters regulates genes transcription across the genome is unclear,and the precise mechanisms still need to be elucidated.H3K4me3 enriched at promoters is essential for maintaining the unmethylated state of Cp G islands,because of the antagonism between H3K4me3 and the ADD domain of DNMT3 family.Using genetic engineering approach,we replaced the DNMT3A2 ADD domain by the PHF2 PHD domain which specifically recognizes H3K4me3.We refer this mutant as “DNMT3A2-PHD”.Here we show that,DNMT3A2-PHD specifically binds to the H3K4me3 enriched promoters across the genome,and establishes DNA methylation at its target regions.Furthermore,we find that extensive establishment of promoter DNA methylation inhibits global gene transcription,while a small subset of genes are activated.Mechanistically,promoter DNA methylation directly inhibits the binding of transcription factors,such as E2F1 and c-Myc,leading to transcription repression.The recruiment of Methyl Cp G binding proteins(MBPs),histone deacetylation and decreased H3K4me3 are not the initial cause for DNMT3A2-PHD-mediated transcription repression.Similar to the function of transcriptional inhibitors,we find that DNA methylation established at the promoters across the genome causes cell apoptosis and cell necrosis.Our findings indicate that the exquisite patterns of promoter DNA methylation is essential for gene transcription and cell fate.