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

被引：10

作者：

Cheishvili, David ^{[1
]}

Christiansen, Steffan ^{[1
,2
]}

Stochinsky, Rebecca ^{[1
]}

Pepin, Anne-Sophie ^{[1
]}

Sapozhnikov, Daniel M. ^{[1
]}

Zhou, Rudy ^{[1
]}

Schmeltzer, Lauren ^{[1
]}

Dymov, Sergey ^{[1
]}

Szyf, Moshe ^{[1
,3
,4
]}

机构：

[1] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada

[2] Aarhus Univ, Dept Biomed, Aarhus, Denmark

[3] McGill Univ, Sch Med, Dept Pharmacol & Therapeut, Sackler Program Epigenet & Dev Psychobiol, Montreal, PQ, Canada

[4] Canadian Inst Adv Res, Dept Pharmacol & Therapeut, Montreal, PQ, Canada

来源：

EPIGENOMICS | 2017年 / 9卷 / 05期

关键词：

5-aza-2 '-deoxycytidine; CRISPR/Cas9; DNA methylation; DNMT1; HNF4A; Illumina; 450k; RNAPII; Ser5; upstream regulators; NUCLEAR FACTOR 4-ALPHA; PROSTATE-CANCER; EXPRESSION; GENES; TUMOR; WIDE; PROLIFERATION; GLUTAMATE; MICRORNAS; PROTEINS;

D O I：

10.2217/epi-2016-0141

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：611 / 633

页数：23

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