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

• Published in: Nature communications Vol. 12; no. 1; p. 4335
• Main Authors: Lattke, Michael, Goldstone, Robert, Ellis, James K., Boeing, Stefan, Jurado-Arjona, Jerónimo, Marichal, Nicolás, MacRae, James I., Berninger, Benedikt, Guillemot, Francois
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.07.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 45; 631/136; 631/337; 631/378; 631/378/2571; 631/378/87; 64; 64/60; Animals; Astrocytes; Astrocytes - cytology; Astrocytes - physiology; Brain; Cell culture; Cell Culture Techniques - methods; Cell Differentiation; Cerebral Cortex - cytology; Chromatin - genetics; Chromatin - metabolism; Chromatin Immunoprecipitation Sequencing; Chromatin remodeling; Epigenesis, Genetic; Fibroblast growth factor 2; Gene Expression; Genes; Homeostasis; Humanities and Social Sciences; In vivo methods and tests; Kinases; Male; Maturation; Mice; Mice, Inbred C57BL; multidisciplinary; Neurological diseases; Science; Science (multidisciplinary); Single-Cell Analysis; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24624-5

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. Astrocytes have functions crucial for brain homeostasis, which are disrupted in many neurological disorders, but how these functions are established during astrocyte maturation is largely unknown. Here the authors show transcriptional and chromatin changes underlying astrocyte maturation in mice and identify transcription factors regulating maturation of cultured astrocytes.