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

Toskas, Konstantinos ; Yaghmaeian-Salmani, Behzad ; Skiteva, Olga ; Paslawski, Wojciech ; Gillberg, Linda ; Skara, Vasiliki ; Antoniou, Irene ; Södersten, Erik ; Svenningsson, Per and Chergui, Karima , et al. (2022) In Science Advances 8(34).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Advances
volume
8
issue
34
article number
eabo1543
pages
20 pages
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85136853169
  • pmid:36026451
ISSN
2375-2548
DOI
10.1126/sciadv.abo1543
language
English
LU publication?
yes
id
6f781c6f-5601-4b93-a0e0-7e40a7a0aeb6
date added to LUP
2022-08-27 18:09:20
date last changed
2025-04-06 03:53:33
@article{6f781c6f-5601-4b93-a0e0-7e40a7a0aeb6,
  abstract     = {{<p>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.</p>}},
  author       = {{Toskas, Konstantinos and Yaghmaeian-Salmani, Behzad and Skiteva, Olga and Paslawski, Wojciech and Gillberg, Linda and Skara, Vasiliki and Antoniou, Irene and Södersten, Erik and Svenningsson, Per and Chergui, Karima and Ringnér, Markus and Perlmann, Thomas and Holmberg, Johan}},
  issn         = {{2375-2548}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{34}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Advances}},
  title        = {{PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons}},
  url          = {{http://dx.doi.org/10.1126/sciadv.abo1543}},
  doi          = {{10.1126/sciadv.abo1543}},
  volume       = {{8}},
  year         = {{2022}},
}