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

Karolina Stępniak,Rafał Guzik,Ilona Grabowicz,Bartłomiej Gielniewski,Bartek Wilczyński,Wiesława Grajkowska,Michał Dramiński,Bartosz Wojtaś,Hanna Kranas,Małgorzata Perycz ,Jakub Mieczkowski,Sylwia Król ,Michal Dabrowski ,Bożena Kamińska ,Tomasz Czernicki,Marta Jardanowska,Agata Dziedzic,Andrzej Marchel,Karolina Sienkiewicz,Magdalena A Machnicka,Klev Diamanti,Marcin Roszkowski,Katarzyna Poleszak,Jan Komorowski,Anna Macioszek,Katarzyna Kotulska

doi:10.1038/s41467-021-23922-2

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.

Highlights

IntroductionCombinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription
Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription
We focused on groups of patients representing major malignancy groups: pilocytic astrocytomas (WHO grade I, PA, n = 11), diffuse astrocytomas (WHO grade II and III, DA, n = 7) and glioblastomas (WHO grade IV, GBM, n = 15)

Summary

Introduction

Combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. 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. Recently researchers began integrating H3K27ac profiles with gene expression, DNA methylomes, copy number variations, and whole exomes demonstrating distinct chromatin and epigenetic profiles in glioblastomas, distinguishing this entity from other brain tumors[17] Combination of those features in a single patient and intersections of acquired profiles in gliomas of different grades have not yet been achieved. We performed a comprehensive analysis of whole genome profiles of open chromatin, histone modifications, DNA methylation and gene expression in tissues of patients using freshly resected gliomas of various malignancy grades.

Methods

Results

Conclusion