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Reconfiguration of Nucleosome Depleted Regions at Distal Regulatory Elements Accompanies DNA Methylation of Enhancers and Insulators in Cancer

Citation

Taberlay, PC and Stratham, AL and Kelly, TK and Clark, SJ and Jones, PA, Reconfiguration of Nucleosome Depleted Regions at Distal Regulatory Elements Accompanies DNA Methylation of Enhancers and Insulators in Cancer, Genome Research, 24 pp. 1421-1432. ISSN 1088-9051 (2014) [Refereed Article]


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Copyright Statement

Copyright 2014 Taberlay et al. Licenced under a Creative Commons License (Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1101/gr.163485.113

Abstract

It is well established that cancer-associated epigenetic repression occurs concomitant with CpG island hypermethylation and loss of nucleosomes at promoters, but the role of nucleosome occupancy and epigenetic reprogramming at distal regulatory elements in cancer is still poorly understood. Here, we evaluate the scope of global epigenetic alterations at enhancers and insulator elements in prostate and breast cancer cells using simultaneous genome-wide mapping of DNA methylation and nucleosome occupancy (NOMe-seq). We find that the genomic location of nucleosome depleted regions (NDRs) is mostly cell type specific and preferentially found at enhancers in normal cells. In cancer cells however, we observe a global reconfiguration of NDRs at distal regulatory elements coupled with a substantial reorganization of the cancer methylome. Aberrant acquisition of nucleosomes at enhancer-associated NDRs is associated with hypermethylation and epigenetic silencing marks and conversely, loss of nucleosomes with demethylation and epigenetic activation. Remarkably, we show that nucleosomes remain strongly organized and phased at many facultative distal regulatory elements, even in the absence of a NDR as an anchor. Finally we find that key transcription factor (TF) binding sites also show extensive peripheral nucleosome phasing, suggesting the potential for TFs to organize NDRs genome-wide and contribute to deregulation of cancer epigenomes. Together our findings suggests that 'decommissioning' of NDRs and TFs at distal regulatory elements in cancer cells is accompanied by DNA hypermethylation susceptibility of enhancers and insulator elements which in turn may contribute to an altered genome-wide architecture and epigenetic deregulation in malignancy.

Item Details

Item Type:Refereed Article
Keywords:enhancer elements, epigenetic remodelling, DNA methylation, nucleosome positions, histone modifications
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Epigenetics (incl. Genome Methylation and Epigenomics)
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Cancer and Related Disorders
Author:Taberlay, PC (Dr Phillippa Taberlay)
ID Code:101260
Year Published:2014
Web of Science® Times Cited:73
Deposited By:Medicine (Discipline)
Deposited On:2015-06-15
Last Modified:2017-12-04
Downloads:226 View Download Statistics

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