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Epigenetic reprogramming shapes the cellular landscape of schwannoma.

ABSTRACT: Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is sufficient for interconversion of neural crest schwannomas to immune-enriched schwannomas through epigenetic and metabolic reprogramming. To define mechanisms underlying schwannoma groups, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of tumor evolution and establish a paradigm of epigenetic and metabolic reprograming of cancer cells that shapes the immune microenvironment in response to radiotherapy.

SUBMITTER: Liu SJ

PROVIDER: S-EPMC10786948 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Epigenetic reprogramming shapes the cellular landscape of schwannoma.

Liu S John SJ Casey-Clyde Tim T Cho Nam Woo NW Swinderman Jason J Pekmezci Melike M Dougherty Mark C MC Foster Kyla K Chen William C WC Villanueva-Meyer Javier E JE Swaney Danielle L DL Vasudevan Harish N HN Choudhury Abrar A Pak Joanna J Breshears Jonathan D JD Lang Ursula E UE Eaton Charlotte D CD Hiam-Galvez Kamir J KJ Stevenson Erica E Chen Kuei-Ho KH Lien Brian V BV Wu David D Braunstein Steve E SE Sneed Penny K PK Magill Stephen T ST Lim Daniel D McDermott Michael W MW Berger Mitchel S MS Perry Arie A Krogan Nevan J NJ Hansen Marlan R MR Spitzer Matthew H MH Gilbert Luke L Theodosopoulos Philip V PV Raleigh David R DR

Nature communications 20240112 1

Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is suffici ...[more]

PMID: 38216587

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Project description:Microglia, the innate immune cells in the central nervous system, exhibit distinct transcriptional profiles across brain regions that are important for facilitating their specialized function. There has been recent interest in identifying the epigenetic modifications associated with these distinct transcriptional profiles, as these may improve our understanding of the underlying mechanisms governing the functional specialization of microglia. One obstacle to achieving this goal is the large number of microglia required to obtain a genome-wide profile for a single histone modification. Given the cellular and regional heterogeneity of the brain, this would require pooling many samples which would impede biological applications that are limited by numbers of available animals. To overcome this obstacle, we have adapted a method of chromatin profiling known as Cleavage Under Targets and Tagmentation (CUT&Tag-Direct) to profile histone modifications associated with regional differences in gene expression throughout the brain reward system. Consistent with previous studies, we find that transcriptional profiles of microglia vary by brain region. However, here we report that these regional differences also exhibit transcriptional network signatures specific to each region. Additionally, we find that these region-dependent network signatures are associated with differential deposition of H3K27ac and H3K7me3, and while the H3K27me3 landscape is remarkably stable across brain regions, the H3K27ac landscape is most consistent with the anatomical location of microglia which explain their distinct transcriptional profiles. Altogether, these findings underscore the established role of H3K27me3 in cell fate determination and support the active role of H3K27ac in the dynamic regulation of microglial gene expression. In this study, we report a molecular and computational framework that can be applied to improve our understanding of the role of epigenetic regulation in microglia in both health and disease, using as few as 2,500 cells per histone mark.

Dataset Information

Epigenetic reprogramming shapes the cellular landscape of schwannoma.

Publications

Epigenetic reprogramming shapes the cellular landscape of schwannoma.

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