DNA methylation controls unmethylated transcription start sites in the genome in trans

TY - JOUR

T1 - DNA methylation controls unmethylated transcription start sites in the genome in trans

AU - Cheishvili, David

AU - Christiansen, Steffan

AU - Stochinsky, Rebecca

AU - Pepin, Anne-Sophie

AU - Sapozhnikov, Daniel M

AU - Zhou, Rudy

AU - Schmeltzer, Lauren

AU - Dymov, Sergey

AU - Szyf, Moshe

PY - 2017/5

Y1 - 2017/5

N2 - AIM: DNA methylation downregulates transcription. However, a large number of genes, which are unmethylated in the promoter region, are inactive. We tested the hypothesis that these genes are regulated by DNA methylation of upstream regulators.METHODS: We inhibited DNMT1 with 5-aza-2'-deoxycytidine or depleted it with shRNA to map the transcription initiation positions controlled by DNMT1 using ChIPseq with RNApolIIser5 antibody. Ingenuity pathway analysis identified potential methylated upstream regulators. Their functional role in controlling unmethylated promoters was determined by CRISPR/Cas9 gene editing.RESULTS: We show that a large group of unmethylated promoters is regulated by DNMT1 through DNA methylation dependent silencing of upstream regulators such as transcription factor HNF4A.CONCLUSION: The landscape of genes regulated by DNA methylation is more wide-ranging than genes downregulated by methylation of their own cis-regulatory sequences; regulation of unmethylated promoters is dependent on the methylation state of upstream trans regulators.

AB - AIM: DNA methylation downregulates transcription. However, a large number of genes, which are unmethylated in the promoter region, are inactive. We tested the hypothesis that these genes are regulated by DNA methylation of upstream regulators.METHODS: We inhibited DNMT1 with 5-aza-2'-deoxycytidine or depleted it with shRNA to map the transcription initiation positions controlled by DNMT1 using ChIPseq with RNApolIIser5 antibody. Ingenuity pathway analysis identified potential methylated upstream regulators. Their functional role in controlling unmethylated promoters was determined by CRISPR/Cas9 gene editing.RESULTS: We show that a large group of unmethylated promoters is regulated by DNMT1 through DNA methylation dependent silencing of upstream regulators such as transcription factor HNF4A.CONCLUSION: The landscape of genes regulated by DNA methylation is more wide-ranging than genes downregulated by methylation of their own cis-regulatory sequences; regulation of unmethylated promoters is dependent on the methylation state of upstream trans regulators.

KW - Journal Article

U2 - 10.2217/epi-2016-0141

DO - 10.2217/epi-2016-0141

M3 - Journal article

C2 - 28470094

SN - 1750-192X

VL - 9

SP - 611

EP - 633

JO - Epigenomics

JF - Epigenomics

IS - 5

ER -