ATRX regulates glial identity and the tumor microenvironment in IDH-mutant glioma

Abstract Background Recent single-cell transcriptomic studies report that IDH-mutant gliomas share a common hierarchy of cellular phenotypes, independent of genetic subtype. However, the genetic differences between IDH-mutant glioma subtypes are prognostic, predictive of response to chemotherapy, an...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Husam Babikir, Lin Wang, Karin Shamardani, Francisca Catalan, Sweta Sudhir, Manish K. Aghi, David R. Raleigh, Joanna J. Phillips, Aaron A. Diaz
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Biology (General) QH301-705.5 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/1f912e20cb9c45bfa17d01103b13cc81
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1f912e20cb9c45bfa17d01103b13cc81
record_format	dspace
spelling	oai:doaj.org-article:1f912e20cb9c45bfa17d01103b13cc812021-11-14T12:42:47ZATRX regulates glial identity and the tumor microenvironment in IDH-mutant glioma10.1186/s13059-021-02535-41474-760Xhttps://doaj.org/article/1f912e20cb9c45bfa17d01103b13cc812021-11-01T00:00:00Zhttps://doi.org/10.1186/s13059-021-02535-4https://doaj.org/toc/1474-760XAbstract Background Recent single-cell transcriptomic studies report that IDH-mutant gliomas share a common hierarchy of cellular phenotypes, independent of genetic subtype. However, the genetic differences between IDH-mutant glioma subtypes are prognostic, predictive of response to chemotherapy, and correlate with distinct tumor microenvironments. Results To reconcile these findings, we profile 22 human IDH-mutant gliomas using scATAC-seq and scRNA-seq. We determine the cell-type-specific differences in transcription factor expression and associated regulatory grammars between IDH-mutant glioma subtypes. We find that while IDH-mutant gliomas do share a common distribution of cell types, there are significant differences in the expression and targeting of transcription factors that regulate glial identity and cytokine elaboration. We knock out the chromatin remodeler ATRX, which suffers loss-of-function alterations in most IDH-mutant astrocytomas, in an IDH-mutant immunocompetent intracranial murine model. We find that both human ATRX-mutant gliomas and murine ATRX-knockout gliomas are more heavily infiltrated by immunosuppressive monocytic-lineage cells derived from circulation than ATRX-intact gliomas, in an IDH-mutant background. ATRX knockout in murine glioma recapitulates gene expression and open chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. Through single-cell cleavage under targets and tagmentation assays and meta-analysis of public data, we show that ATRX loss leads to a global depletion in CCCTC-binding factor association with DNA, gene dysregulation along associated chromatin loops, and protection from therapy-induced senescence. Conclusions These studies explain how IDH-mutant gliomas from different subtypes maintain distinct phenotypes and tumor microenvironments despite a common lineage hierarchy.Husam BabikirLin WangKarin ShamardaniFrancisca CatalanSweta SudhirManish K. AghiDavid R. RaleighJoanna J. PhillipsAaron A. DiazBMCarticleBiology (General)QH301-705.5GeneticsQH426-470ENGenome Biology, Vol 22, Iss 1, Pp 1-22 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5 Genetics QH426-470
spellingShingle	Biology (General) QH301-705.5 Genetics QH426-470 Husam Babikir Lin Wang Karin Shamardani Francisca Catalan Sweta Sudhir Manish K. Aghi David R. Raleigh Joanna J. Phillips Aaron A. Diaz ATRX regulates glial identity and the tumor microenvironment in IDH-mutant glioma
description	Abstract Background Recent single-cell transcriptomic studies report that IDH-mutant gliomas share a common hierarchy of cellular phenotypes, independent of genetic subtype. However, the genetic differences between IDH-mutant glioma subtypes are prognostic, predictive of response to chemotherapy, and correlate with distinct tumor microenvironments. Results To reconcile these findings, we profile 22 human IDH-mutant gliomas using scATAC-seq and scRNA-seq. We determine the cell-type-specific differences in transcription factor expression and associated regulatory grammars between IDH-mutant glioma subtypes. We find that while IDH-mutant gliomas do share a common distribution of cell types, there are significant differences in the expression and targeting of transcription factors that regulate glial identity and cytokine elaboration. We knock out the chromatin remodeler ATRX, which suffers loss-of-function alterations in most IDH-mutant astrocytomas, in an IDH-mutant immunocompetent intracranial murine model. We find that both human ATRX-mutant gliomas and murine ATRX-knockout gliomas are more heavily infiltrated by immunosuppressive monocytic-lineage cells derived from circulation than ATRX-intact gliomas, in an IDH-mutant background. ATRX knockout in murine glioma recapitulates gene expression and open chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. Through single-cell cleavage under targets and tagmentation assays and meta-analysis of public data, we show that ATRX loss leads to a global depletion in CCCTC-binding factor association with DNA, gene dysregulation along associated chromatin loops, and protection from therapy-induced senescence. Conclusions These studies explain how IDH-mutant gliomas from different subtypes maintain distinct phenotypes and tumor microenvironments despite a common lineage hierarchy.
format	article
author	Husam Babikir Lin Wang Karin Shamardani Francisca Catalan Sweta Sudhir Manish K. Aghi David R. Raleigh Joanna J. Phillips Aaron A. Diaz
author_facet	Husam Babikir Lin Wang Karin Shamardani Francisca Catalan Sweta Sudhir Manish K. Aghi David R. Raleigh Joanna J. Phillips Aaron A. Diaz
author_sort	Husam Babikir
title	ATRX regulates glial identity and the tumor microenvironment in IDH-mutant glioma
title_short	ATRX regulates glial identity and the tumor microenvironment in IDH-mutant glioma
title_full	ATRX regulates glial identity and the tumor microenvironment in IDH-mutant glioma
title_fullStr	ATRX regulates glial identity and the tumor microenvironment in IDH-mutant glioma
title_full_unstemmed	ATRX regulates glial identity and the tumor microenvironment in IDH-mutant glioma
title_sort	atrx regulates glial identity and the tumor microenvironment in idh-mutant glioma
publisher	BMC
publishDate	2021
url	https://doaj.org/article/1f912e20cb9c45bfa17d01103b13cc81
work_keys_str_mv	AT husambabikir atrxregulatesglialidentityandthetumormicroenvironmentinidhmutantglioma AT linwang atrxregulatesglialidentityandthetumormicroenvironmentinidhmutantglioma AT karinshamardani atrxregulatesglialidentityandthetumormicroenvironmentinidhmutantglioma AT franciscacatalan atrxregulatesglialidentityandthetumormicroenvironmentinidhmutantglioma AT swetasudhir atrxregulatesglialidentityandthetumormicroenvironmentinidhmutantglioma AT manishkaghi atrxregulatesglialidentityandthetumormicroenvironmentinidhmutantglioma AT davidrraleigh atrxregulatesglialidentityandthetumormicroenvironmentinidhmutantglioma AT joannajphillips atrxregulatesglialidentityandthetumormicroenvironmentinidhmutantglioma AT aaronadiaz atrxregulatesglialidentityandthetumormicroenvironmentinidhmutantglioma
_version_	1718429033685843968

ATRX regulates glial identity and the tumor microenvironment in IDH-mutant glioma

Ejemplares similares