Extensive transcriptional and chromatin changes underlie astrocyte maturation in vivo and in culture

Michael Lattke; Robert Goldstone; James K Ellis; Stefan Boeing; Jeronimo Jurado Arjona; Nicolas Marichal Negrin; James I McRae; Benedikt Berninger; Francois Guillemot

doi:10.1038/s41467-021-24624-5

Extensive transcriptional and chromatin changes underlie astrocyte maturation in vivo and in culture

Michael Lattke, Robert Goldstone, James K Ellis, Stefan Boeing, Jeronimo Jurado Arjona, Nicolas Marichal Negrin, James I McRae, Benedikt Berninger, Francois Guillemot

Developmental Neurobiology

Francis Crick Institute

Research output: Contribution to journal › Article › peer-review

61 Citations (Scopus)

Abstract

Astrocytes have essential functions in brain homeostasis that are established late in differentiation, but the mechanisms underlying the functional maturation of astrocytes are not well understood. Here we identify extensive transcriptional changes that occur during murine astrocyte maturation in vivo that are accompanied by chromatin remodelling at enhancer elements. Investigating astrocyte maturation in a cell culture model revealed that in vitro differentiated astrocytes lack expression of many mature astrocyte-specific genes, including genes for the transcription factors Rorb, Dbx2, Lhx2 and Fezf2. Forced expression of these factors in vitro induces distinct sets of mature astrocyte-specific transcripts. Culturing astrocytes in a three-dimensional matrix containing FGF2 induces expression of Rorb, Dbx2 and Lhx2 and improves astrocyte maturity based on transcriptional and chromatin profiles. Therefore, extrinsic signals orchestrate the expression of multiple intrinsic regulators, which in turn induce in a modular manner the transcriptional and chromatin changes underlying astrocyte maturation.

Original language	English
Article number	4335
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24624-5
Publication status	Published - Dec 2021

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title = "Extensive transcriptional and chromatin changes underlie astrocyte maturation in vivo and in culture",

abstract = "Astrocytes have essential functions in brain homeostasis that are established late in differentiation, but the mechanisms underlying the functional maturation of astrocytes are not well understood. Here we identify extensive transcriptional changes that occur during murine astrocyte maturation in vivo that are accompanied by chromatin remodelling at enhancer elements. Investigating astrocyte maturation in a cell culture model revealed that in vitro differentiated astrocytes lack expression of many mature astrocyte-specific genes, including genes for the transcription factors Rorb, Dbx2, Lhx2 and Fezf2. Forced expression of these factors in vitro induces distinct sets of mature astrocyte-specific transcripts. Culturing astrocytes in a three-dimensional matrix containing FGF2 induces expression of Rorb, Dbx2 and Lhx2 and improves astrocyte maturity based on transcriptional and chromatin profiles. Therefore, extrinsic signals orchestrate the expression of multiple intrinsic regulators, which in turn induce in a modular manner the transcriptional and chromatin changes underlying astrocyte maturation. ",

author = "Michael Lattke and Robert Goldstone and Ellis, {James K} and Stefan Boeing and {Jurado Arjona}, Jeronimo and {Marichal Negrin}, Nicolas and McRae, {James I} and Benedikt Berninger and Francois Guillemot",

note = "Funding Information: We thank Maria del Mar Masdeu and Lan Chen for technical support, the Science Technology Platforms of the Francis Crick Institute and in particular Amelia Edwards and Deb Jackson from the Advanced Sequencing Facility, Harshil Patel and Nourdine Bah from Bioinformatics & Biostatistics and the Biological Research Facility for their support. We also thank the members of the Crick Scientific Computing Software Development & Machine Learning Team, particularly Amy Strange, Luke Nightingale, Jude Pinnock and Marc Pollitt for excellent technical support. This work was supported by a grant from the Medical Research Council to F.G. (FC0010408), by core funding to the Francis Crick Institute from Cancer Research UK, the Medical Research Council and the Wellcome Trust (FC0010089, FC001002), as well as a Wellcome Trust grant to B.B. (206410/Z/17/Z). M.L. was supported by a research fellowship from the German Research Foundation (DFG) (LA 4031/1-1). N.M. was supported by a fellowship from the Human Frontiers Science Program (HFSP Long-Term Fellowship, LT000646/2015) and J.J.-A. by a research fellowship by the European Commission (Marie Sk{\l}odowska-Curie Action). Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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AU - Lattke, Michael

AU - Goldstone, Robert

AU - Ellis, James K

AU - Boeing, Stefan

AU - Jurado Arjona, Jeronimo

AU - Marichal Negrin, Nicolas

AU - McRae, James I

AU - Berninger, Benedikt

AU - Guillemot, Francois

N1 - Funding Information: We thank Maria del Mar Masdeu and Lan Chen for technical support, the Science Technology Platforms of the Francis Crick Institute and in particular Amelia Edwards and Deb Jackson from the Advanced Sequencing Facility, Harshil Patel and Nourdine Bah from Bioinformatics & Biostatistics and the Biological Research Facility for their support. We also thank the members of the Crick Scientific Computing Software Development & Machine Learning Team, particularly Amy Strange, Luke Nightingale, Jude Pinnock and Marc Pollitt for excellent technical support. This work was supported by a grant from the Medical Research Council to F.G. (FC0010408), by core funding to the Francis Crick Institute from Cancer Research UK, the Medical Research Council and the Wellcome Trust (FC0010089, FC001002), as well as a Wellcome Trust grant to B.B. (206410/Z/17/Z). M.L. was supported by a research fellowship from the German Research Foundation (DFG) (LA 4031/1-1). N.M. was supported by a fellowship from the Human Frontiers Science Program (HFSP Long-Term Fellowship, LT000646/2015) and J.J.-A. by a research fellowship by the European Commission (Marie Skłodowska-Curie Action). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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N2 - Astrocytes have essential functions in brain homeostasis that are established late in differentiation, but the mechanisms underlying the functional maturation of astrocytes are not well understood. Here we identify extensive transcriptional changes that occur during murine astrocyte maturation in vivo that are accompanied by chromatin remodelling at enhancer elements. Investigating astrocyte maturation in a cell culture model revealed that in vitro differentiated astrocytes lack expression of many mature astrocyte-specific genes, including genes for the transcription factors Rorb, Dbx2, Lhx2 and Fezf2. Forced expression of these factors in vitro induces distinct sets of mature astrocyte-specific transcripts. Culturing astrocytes in a three-dimensional matrix containing FGF2 induces expression of Rorb, Dbx2 and Lhx2 and improves astrocyte maturity based on transcriptional and chromatin profiles. Therefore, extrinsic signals orchestrate the expression of multiple intrinsic regulators, which in turn induce in a modular manner the transcriptional and chromatin changes underlying astrocyte maturation.

AB - Astrocytes have essential functions in brain homeostasis that are established late in differentiation, but the mechanisms underlying the functional maturation of astrocytes are not well understood. Here we identify extensive transcriptional changes that occur during murine astrocyte maturation in vivo that are accompanied by chromatin remodelling at enhancer elements. Investigating astrocyte maturation in a cell culture model revealed that in vitro differentiated astrocytes lack expression of many mature astrocyte-specific genes, including genes for the transcription factors Rorb, Dbx2, Lhx2 and Fezf2. Forced expression of these factors in vitro induces distinct sets of mature astrocyte-specific transcripts. Culturing astrocytes in a three-dimensional matrix containing FGF2 induces expression of Rorb, Dbx2 and Lhx2 and improves astrocyte maturity based on transcriptional and chromatin profiles. Therefore, extrinsic signals orchestrate the expression of multiple intrinsic regulators, which in turn induce in a modular manner the transcriptional and chromatin changes underlying astrocyte maturation.

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DO - 10.1038/s41467-021-24624-5

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ER -

Extensive transcriptional and chromatin changes underlie astrocyte maturation in vivo and in culture

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