Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

Abstract

Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

The role of epigenetic modifications, long-range contacts, enhancers and topologically associating domains in the regulation of glioma grade-specific genes

“…Additionally, we discovered enhancers with H3K27ac signals that were significantly different in glioma of various grades, indicating that their activity changed as the malignancy grade progressed. The correlation between enhancer H3K27 acetylation and the expression levels of their target genes ranged from 0.27 to 0.43 in gliomas, which was higher than the correlation between all active, non-DE genes in gliomas 12 . Stępniak and coworkers 12 have analysed the same dataset and the correlations of expression of all active genes with H3K27ac of their contacting enhancers were rather low: 0.1–0.25.…”

“…The correlation between enhancer H3K27 acetylation and the expression levels of their target genes ranged from 0.27 to 0.43 in gliomas, which was higher than the correlation between all active, non-DE genes in gliomas 12 . Stępniak and coworkers 12 have analysed the same dataset and the correlations of expression of all active genes with H3K27ac of their contacting enhancers were rather low: 0.1–0.25. Altogether, these findings suggest that a subset of genes identified in this study is strongly regulated by active enhancers and may play a role in gliomagenesis.…”

“…Following the observation that not all of the enhancers are active in all patients but they are rather patient-specific 12 , we looked for enhancers that were differentially active in glioma of various grades (Fig. 3 C; Supplementary Fig.…”

“…Methylation of a set of specific cytosines allows for highly accurate prediction of overall survival of glioma patients from TCGA datasets 11 . The recent study of Stępniak et al 12 characterized the landscape of open chromatin and histone marks in gliomas of different grades providing a rich resource for further exploration. Gene expression patterns in glioma of different grades have been correlated with epigenetic marks depositions in the transcription start site (TSS) regions.…”

“…In particular, the higher signals of H3K4me3 have been observed in pilocytic astrocytomas (PA) than in diffuse astrocytomas (DA) and glioblastomas (GBM). In this study we took advantage of that data resource 12 .…”