Comprehensive analysis of the DNA methylation mutant Hells-/- reveals de-repression of repeat elements and redundant pathway for silencing of protein-coding genes

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	NCI	CHROM-2

* FARE Award Winner

Authors

• W Yu
• C McIntosh
• R Lister
• I Zhu
• Y Han
• J Ren
• D Landsman
• E Lee
• J.R Ecker
• K Muegge

Abstract

Cytosine methylation is critical in mammalian development and plays a role in diverse biologic processes including genomic imprinting and silencing of repeat elements. Several factors control DNA methylation in early embryogenesis, but their precise role in the establishment of DNA methylation remains unclear. We have generated a comprehensive methylation map in fibroblasts derived from the murine mutant Hells-/-, which can influence de novo methylation of retroviral sequences and endogenous genes. We report here a role for Hells in the establishment of cytosine methylation comprising a nuclear compartment that is in part defined by Lamin B1 attachment regions. Despite widespread loss of cytosine methylation at regulatory sites, including promoter regions of protein coding genes and non-coding RNA genes, overall transcript abundance levels in the Hells-/- are similar to those in wild type cells. Increases of the histone modification H3K27me3 at a subset of promoter regions suggest redundancy of epigenetic silencing mechanisms. Furthermore, Hells modulates CG methylation patterns at all classes of repeat elements and is critical for transcriptional silencing of a subset of repeat elements. Overall, we provide a detailed analysis of gene expression in relation to DNA methylation alterations, contributing to our understanding of the biological role of cytosine methylation.

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