학술논문
DNA methylation landscapes in DIPG reveal methylome variability that can be modified pharmacologically.
Document Type
Academic Journal
Author
Tetens AR; Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Martin AM; Pediatric Hematology-Oncology, Albert Einstein College of Medicine, Bronx, New York, USA.; Arnold A; Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Novak OV; Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Idrizi A; Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Tryggvadottir R; Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Craig-Schwartz J; Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Liapodimitri A; Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Lunsford K; Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Barbato MI; Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Eberhart CG; Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Resnick AC; Center for Data-Driven Discovery in Biomedicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Division of Neurosurgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Raabe EH; Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Koldobskiy MA; Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Source
Publisher: Oxford University Press Country of Publication: England NLM ID: 101755003 Publication Model: eCollection Cited Medium: Internet ISSN: 2632-2498 (Electronic) Linking ISSN: 26322498 NLM ISO Abbreviation: Neurooncol Adv Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
Background: Diffuse intrinsic pontine glioma (DIPG) is a uniformly lethal brainstem tumor of childhood, driven by histone H3 K27M mutation and resultant epigenetic dysregulation. Epigenomic analyses of DIPG have shown global loss of repressive chromatin marks accompanied by DNA hypomethylation. However, studies providing a static view of the epigenome do not adequately capture the regulatory underpinnings of DIPG cellular heterogeneity and plasticity.
Methods: To address this, we performed whole-genome bisulfite sequencing on a large panel of primary DIPG specimens and applied a novel framework for analysis of DNA methylation variability, permitting the derivation of comprehensive genome-wide DNA methylation potential energy landscapes that capture intrinsic epigenetic variation.
Results: We show that DIPG has a markedly disordered epigenome with increasingly stochastic DNA methylation at genes regulating pluripotency and developmental identity, potentially enabling cells to sample diverse transcriptional programs and differentiation states. The DIPG epigenetic landscape was responsive to treatment with the hypomethylating agent decitabine, which produced genome-wide demethylation and reduced the stochasticity of DNA methylation at active enhancers and bivalent promoters. Decitabine treatment elicited changes in gene expression, including upregulation of immune signaling such as the interferon response, STING, and MHC class I expression, and sensitized cells to the effects of histone deacetylase inhibition.
Conclusions: This study provides a resource for understanding the epigenetic instability that underlies DIPG heterogeneity. It suggests the application of epigenetic therapies to constrain the range of epigenetic states available to DIPG cells, as well as the use of decitabine in priming for immune-based therapies.
Competing Interests: The authors declare that they have no competing interests.
(© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
Methods: To address this, we performed whole-genome bisulfite sequencing on a large panel of primary DIPG specimens and applied a novel framework for analysis of DNA methylation variability, permitting the derivation of comprehensive genome-wide DNA methylation potential energy landscapes that capture intrinsic epigenetic variation.
Results: We show that DIPG has a markedly disordered epigenome with increasingly stochastic DNA methylation at genes regulating pluripotency and developmental identity, potentially enabling cells to sample diverse transcriptional programs and differentiation states. The DIPG epigenetic landscape was responsive to treatment with the hypomethylating agent decitabine, which produced genome-wide demethylation and reduced the stochasticity of DNA methylation at active enhancers and bivalent promoters. Decitabine treatment elicited changes in gene expression, including upregulation of immune signaling such as the interferon response, STING, and MHC class I expression, and sensitized cells to the effects of histone deacetylase inhibition.
Conclusions: This study provides a resource for understanding the epigenetic instability that underlies DIPG heterogeneity. It suggests the application of epigenetic therapies to constrain the range of epigenetic states available to DIPG cells, as well as the use of decitabine in priming for immune-based therapies.
Competing Interests: The authors declare that they have no competing interests.
(© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)