PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons

How neurons can maintain cellular identity over an entire life span remains largely unknown. Here, we show that maintenance of identity in differentiated dopaminergic and serotonergic neurons is critically reliant on the Polycomb repressive complex 2 (PRC2). Deletion of the obligate PRC2 component,...

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Published in:Science advances 2022-08, Vol.8 (34), p.eabo1543-eabo1543
Main Authors: Toskas, Konstantinos, Yaghmaeian-Salmani, Behzad, Skiteva, Olga, Paslawski, Wojciech, Gillberg, Linda, Skara, Vasiliki, Antoniou, Irene, Södersten, Erik, Svenningsson, Per, Chergui, Karima, Ringnér, Markus, Perlmann, Thomas, Holmberg, Johan
Format: Article
Language:English
Subjects:
Biochemistry and Molecular Biology
Bioinformatics and Systems Biology
Bioinformatik och systembiologi
Biokemi och molekylärbiologi
Biologi
Biological Sciences
Biomedicine and Life Sciences
Cell Biology
Cellbiologi
Cellular Neuroscience
Medicin och hälsovetenskap
Natural Sciences
Naturvetenskap
Neuroscience
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Summary:How neurons can maintain cellular identity over an entire life span remains largely unknown. Here, we show that maintenance of identity in differentiated dopaminergic and serotonergic neurons is critically reliant on the Polycomb repressive complex 2 (PRC2). Deletion of the obligate PRC2 component, Eed , in these neurons resulted in global loss of H3K27me3, followed by a gradual activation of genes harboring both H3K27me3 and H3K9me3 modifications. Notably, H3K9me3 was lost at these PRC2 targets before gene activation. Neuronal survival was not compromised; instead, there was a reduction in subtype-specific gene expression and a progressive impairment of dopaminergic and serotonergic neuronal function, leading to behavioral deficits characteristic of Parkinson’s disease and anxiety. Single-cell analysis revealed subtype-specific vulnerability to loss of PRC2 repression in dopamine neurons of the substantia nigra. Our study reveals that a PRC2-dependent nonpermissive chromatin state is essential to maintain the subtype identity and function of dopaminergic and serotonergic neurons. Epigenetic control of transcriptional stability maintains identity and function in dopaminergic and serotonergic neurons.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abo1543