OVOL2 sustains postnatal thymic epithelial cell identity
© 2023. The Author(s)..
Distinct pathways and molecules may support embryonic versus postnatal thymic epithelial cell (TEC) development and maintenance. Here, we identify a mechanism by which TEC numbers and function are maintained postnatally. A viable missense allele (C120Y) of Ovol2, expressed ubiquitously or specifically in TECs, results in lymphopenia, in which T cell development is compromised by loss of medullary TECs and dysfunction of cortical TECs. We show that the epithelial identity of TECs is aberrantly subverted towards a mesenchymal state in OVOL2-deficient mice. We demonstrate that OVOL2 inhibits the epigenetic regulatory BRAF-HDAC complex, specifically disrupting RCOR1-LSD1 interaction. This causes inhibition of LSD1-mediated H3K4me2 demethylation, resulting in chromatin accessibility and transcriptional activation of epithelial genes. Thus, OVOL2 controls the epigenetic landscape of TECs to enforce TEC identity. The identification of a non-redundant postnatal mechanism for TEC maintenance offers an entry point to understanding thymic involution, which normally begins in early adulthood.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 27. Nov., Seite 7786 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhong, Xue [VerfasserIn] |
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| Links: |
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| Themen: |
EC 1.14.11.- |
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| Anmerkungen: |
Date Completed 01.12.2023 Date Revised 01.12.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-43456-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM365033316 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a Distinct pathways and molecules may support embryonic versus postnatal thymic epithelial cell (TEC) development and maintenance. Here, we identify a mechanism by which TEC numbers and function are maintained postnatally. A viable missense allele (C120Y) of Ovol2, expressed ubiquitously or specifically in TECs, results in lymphopenia, in which T cell development is compromised by loss of medullary TECs and dysfunction of cortical TECs. We show that the epithelial identity of TECs is aberrantly subverted towards a mesenchymal state in OVOL2-deficient mice. We demonstrate that OVOL2 inhibits the epigenetic regulatory BRAF-HDAC complex, specifically disrupting RCOR1-LSD1 interaction. This causes inhibition of LSD1-mediated H3K4me2 demethylation, resulting in chromatin accessibility and transcriptional activation of epithelial genes. Thus, OVOL2 controls the epigenetic landscape of TECs to enforce TEC identity. The identification of a non-redundant postnatal mechanism for TEC maintenance offers an entry point to understanding thymic involution, which normally begins in early adulthood | ||
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| 700 | 1 | |a Peddada, Nagesh |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jianhui |e verfasserin |4 aut | |
| 700 | 1 | |a Moresco, James J |e verfasserin |4 aut | |
| 700 | 1 | |a Zhan, Xiaowei |e verfasserin |4 aut | |
| 700 | 1 | |a Shelton, John M |e verfasserin |4 aut | |
| 700 | 1 | |a SoRelle, Jeffrey A |e verfasserin |4 aut | |
| 700 | 1 | |a Keller, Katie |e verfasserin |4 aut | |
| 700 | 1 | |a Lazaro, Danielle Renee |e verfasserin |4 aut | |
| 700 | 1 | |a Moresco, Eva Marie Y |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Jin Huk |e verfasserin |4 aut | |
| 700 | 1 | |a Beutler, Bruce |e verfasserin |4 aut | |
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