Genome-wide methylome and chromatin interactome identify abnormal enhancer to be risk factor of breast cancer.

Yuan Wang,Li Wang,Li-Jun Di,Da-Peng Hao,Jing-Jing Li

doi:10.18632/oncotarget.18348

Yuan Wang, Li Wang + Show 3 more

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https://doi.org/10.18632/oncotarget.18348

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Journal: Oncotarget	Publication Date: Jun 2, 2017
Citations: 8	License type: cc-by

Affiliation: City University of Macau, University of Macau

Abstract

Enhancer is critical cis regulatory elements in gene expression. To understand whether and how the aberrant enhancer activation may contribute to cancer risk, the differentially methylated enhancers (eDMRs) in normal and malignant breast tissues were identified and analyzed. By incorporating genome-wide chromatin interaction, integrated analysis of eDMRs and target gene expression identified 1,272 enhancer-promoter pairs. Surprisingly, two functionally distinct groups of genes were identified in these pairs, one showing better correlation to enhancer methylation (eRGs) and the other showing better correlation to promoter methylation (pRGs), and the former group is functionally enriched with cancer related genes. Moreover, enhancer methylation based clustering of breast cancer samples is capable of discriminating basal breast cancer from other subtypes. By correlating enhancer methylation status to patient survival, 345 enhancers show the impact on the disease outcome and the majority of their target genes are important regulators of cell survival pathways including known cancer related genes. Together, these results suggest reactivation of enhancers in cancer cells has the add-on effect and contributes to cancer risk in combination.

Highlights

Gene expression is a dynamic process and is precisely regulated by many factors through mainly two layers of mechanisms including the regulation of the chromatin compaction and the regulation of the interactions between transcriptional machinery and gene regulatory elements [1,2,3]
By examining enhancers methylation status in breast cancer patient samples, we found that gene expression has a significant correlation to their enhancer methylation, providing important evidence that aberrantly reduced enhancer methylation contributes to the differential expression of cancer-related genes, as well as the survival risk of patients
Of the enhancers are differentially methylated between cancer and normal samples, and nearly 70% of them are hypomethylated in the tumor, which suggested enhancers tends to be active in the tumor. (Figure 1A)

Summary

Introduction

Gene expression is a dynamic process and is precisely regulated by many factors through mainly two layers of mechanisms including the regulation of the chromatin compaction and the regulation of the interactions between transcriptional machinery and gene regulatory elements [1,2,3]. Chromatin compaction status determines if the gene regulatory elements are accessible to transcriptional factors (TFs) [4,5,6,7,8,9]. There is controversial data regarding the importance of RNA polII binding at enhancer in RNA polII recruitment to gene promoter, the enhancer does increase the pol II enrichment at the promoter and boost up the transcription activity [16, 17]. ChIA-PET, as a newly developed method, can capture the DNA fragments that contact to each other mediated by proteins [18, 19]

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