Cancer-specific epigenome identifies oncogenic hijacking by nuclear factor I family proteins for medulloblastoma progression.

in Developmental cell by Ryo Shiraishi, Gabriele Cancila, Kohei Kumegawa, Jacob Torrejon, Irene Basili, Flavia Bernardi, Patricia Benites Goncalves da Silva, Wanchen Wang, Owen Chapman, Liying Yang, Maki Jami, Kayo Nishitani, Yukimi Arai, Zhize Xiao, Hua Yu, Valentina Lo Re, Véronique Marsaud, Julie Talbot, Bérangère Lombard, Damarys Loew, Maho Jingu, Konstantin Okonechnikov, Masaki Sone, Norio Motohashi, Yoshitsugu Aoki, Stefan M Pfister, Lukas Chavez, Mikio Hoshino, Reo Maruyama, Olivier Ayrault, Daisuke Kawauchi

TLDR

  • The study looks at how the way genes are turned on and off changes in a type of brain tumor called medulloblastoma. They found that certain proteins that help cells decide what to become are turned on in these tumors. They also found that when they stopped these proteins from working, the tumors stopped growing.

Abstract

Normal cells coordinate proliferation and differentiation by precise tuning of gene expression based on the dynamic shifts of the epigenome throughout the developmental timeline. Although non-mutational epigenetic reprogramming is an emerging hallmark of cancer, the epigenomic shifts that occur during the transition from normal to malignant cells remain elusive. Here, we capture the epigenomic changes that occur during tumorigenesis in a prototypic embryonal brain tumor, medulloblastoma. By comparing the epigenomes of the different stages of transforming cells in mice, we identify nuclear factor I family of transcription factors, known to be cell fate determinants in development, as oncogenic regulators in the epigenomes of precancerous and cancerous cells. Furthermore, genetic and pharmacological inhibition of NFIB validated a crucial role of this transcription factor by disrupting the cancer epigenome in medulloblastoma. Thus, this study exemplifies how epigenomic changes contribute to tumorigenesis via non-mutational mechanisms involving developmental transcription factors.

Overview

  • The study investigates the epigenomic changes that occur during tumorigenesis in a prototypic embryonal brain tumor, medulloblastoma, and identifies nuclear factor I family of transcription factors as oncogenic regulators in the epigenomes of precancerous and cancerous cells. The study aims to understand how epigenomic changes contribute to tumorigenesis via non-mutational mechanisms involving developmental transcription factors.

Comparative Analysis & Findings

  • The study compares the epigenomes of different stages of transforming cells in mice and identifies nuclear factor I family of transcription factors as oncogenic regulators in the epigenomes of precancerous and cancerous cells. The study also validates the crucial role of this transcription factor by disrupting the cancer epigenome in medulloblastoma through genetic and pharmacological inhibition.

Implications and Future Directions

  • The study's findings highlight the importance of epigenomic changes in tumorigenesis and suggest that non-mutational mechanisms involving developmental transcription factors may play a crucial role in cancer development. Future research could explore the role of other developmental transcription factors in tumorigenesis and investigate the potential of targeting these factors for cancer treatment.
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