Invited Review: The role and contribution of transcriptional enhancers in brain cancer

Abstract

2020) Neuropathology and Applied Neurobiology 46, 48-56 The role and contribution of transcriptional enhancers in brain cancer Genetic alterations identified across several paediatric and adult brain tumours reveal recurrent disruption of active chromatin landscapes and dysregulation of transcriptional programmes. Noncoding elements, specifically enhancers, are central to these mechanisms, and are influenced by developmental and neural gene regulatory signatures. Epigenomic and transcriptomic methods and techniques have facilitated detection of active enhancers, and characterization of brain tumours integrated with genomic structural information. These datasets have provided new insights into the mechanisms of transcriptional control that are profoundly altered in childhood and adult brain cancer; offering new ideas and molecular targets for therapeutic intervention. This review summarizes recent advances in our understanding of active transcriptional programmes of brain cancer, their impact on tumour development, and research areas for further exploration.

Epigenomic landscape and 3D genome structure in pediatric high-grade glioma

“…Recent studies also found that SOX2 - and OLIG1 - positive progenitor cells give rise to both H3K27M DIPG and adult GBM ( 7 , 22 ). In addition, OLIG2 and RUNX2 were found to robustly segregate two distinct glioma cell populations with differential response to drug therapy ( 23 ), suggesting that these factors might contribute uniquely to therapeutic resistance ( 24 ).…”

Epigenetic Targeting of Mcl-1 Is Synthetically Lethal with Bcl-xL/Bcl-2 Inhibition in Model Systems of Glioblastoma

“…To date, there are numerous histone-modifying enzymes that can be categorized in writers, erasers, and readers. With regard to these chemical modifications, acetylation and methylation may be the most abundant ones when considering the currently available literature [ 30 ]. The differences in post translational modifications of histones establishes an epigenetic code and orchestrates the accessibility of the chromatin, thereby regulating transcription [ 29 ].…”

“…The concept of super-enhancers has recently emerged and is an interesting model to provide an epigenetic explanation as to why certain pathways are up-regulated in cancers. Enhancers are regulators of gene expression that are several kilo bases down- or up-stream of the transcriptional start site to control transcription (loop formation) and their disruption may be an emerging therapeutic opportunity [ 30 ]. Here, we found that Mcl-1 expression correlated with the presence of a super-enhancer region in glioblastoma models, providing an explanation why this protein is increased in gliomas.…”

Childhood brain tumours as epigenetic diseases

“…These concepts are further explored by Steve Mack and colleagues as they relate to the key consequence of epigenetic dysregulation – the disruption of key gene expression programmes[9]. In particular, they explore a common mechanism of transcriptional control that is abrogated in a range of childhood brain tumours, the concept of enhancer and super enhancer regions found outside of gene promoters, but which play a crucial role in the regulation of gene expression [10].…”