Chromatin landscapes reveal developmentally encoded transcriptional states that define human glioblastoma.

in The Journal of experimental medicine by Stephen C Mack, Irtisha Singh, Xiuxing Wang, Rachel Hirsch, Quilian Wu, Rosie Villagomez, Jean A Bernatchez, Zhe Zhu, Ryan C Gimple, Leo J Y Kim, Andrew Morton, Sisi Lai, Zhixin Qiu, Briana C Prager, Kelsey C Bertrand, Clarence Mah, Wenchao Zhou, Christine Lee, Gene H Barnett, Michael A Vogelbaum, Andrew E Sloan, Lukas Chavez, Shideng Bao, Peter C Scacheri, Jair L Siqueira-Neto, Charles Y Lin, Jeremy N Rich

TLDR

  • This study identified distinct transcription factor regulatory programs in glioblastoma stem cells that are associated with poor clinical outcomes. The research suggests that targeting these programs may be a viable therapeutic approach.

Abstract

Glioblastoma is an incurable brain cancer characterized by high genetic and pathological heterogeneity. Here, we mapped active chromatin landscapes with gene expression, whole exomes, copy number profiles, and DNA methylomes across 44 patient-derived glioblastoma stem cells (GSCs), 50 primary tumors, and 10 neural stem cells (NSCs) to identify essential super-enhancer (SE)-associated genes and the core transcription factors that establish SEs and maintain GSC identity. GSCs segregate into two groups dominated by distinct enhancer profiles and unique developmental core transcription factor regulatory programs. Group-specific transcription factors enforce GSC identity; they exhibit higher activity in glioblastomas versus NSCs, are associated with poor clinical outcomes, and are required for glioblastoma growth in vivo. Although transcription factors are commonly considered undruggable, group-specific enhancer regulation of the MAPK/ERK pathway predicts sensitivity to MEK inhibition. These data demonstrate that transcriptional identity can be leveraged to identify novel dependencies and therapeutic approaches.

Overview

  • The study aimed to identify essential super-enhancer (SE)-associated genes and transcription factors that establish glioblastoma stem cell (GSC) identity and fuel glioblastoma growth.
  • The researchers mapped active chromatin landscapes, gene expression, whole exomes, copy number profiles, and DNA methylomes across 44 patient-derived GSCs, 50 primary tumors, and 10 neural stem cells (NSCs) to achieve this goal.
  • The study focused on understanding glioblastoma's unique transcriptional identity and its potential for treating this incurable brain cancer.

Comparative Analysis & Findings

  • The study found that GSCs segregate into two groups based on distinct enhancer profiles and transcription factor regulatory programs.
  • Group-specific transcription factors were found to be more active in glioblastomas than in NSCs, associated with poor clinical outcomes, and required for glioblastoma growth in vivo.
  • The researchers discovered that group-specific enhancer regulation of the MAPK/ERK pathway predicts sensitivity to MEK inhibition, providing a potential therapeutic approach.

Implications and Future Directions

  • The study demonstrates the potential for leveraging transcriptional identity to identify novel dependencies and therapeutic approaches for glioblastoma.
  • Future studies can build on this research by exploring the dynamics of transcription factor regulation during glioblastoma development and progression.
  • The findings may also inform the development of targeted therapies that disrupt glioblastoma-specific transcriptional programs.
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