OVOL2 sustains postnatal thymic epithelial cell identity
Abstract 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 s...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43456-z |
| _version_ | 1797414608929030144 |
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| author | Xue Zhong Nagesh Peddada Jianhui Wang James J. Moresco Xiaowei Zhan John M. Shelton Jeffrey A. SoRelle Katie Keller Danielle Renee Lazaro Eva Marie Y. Moresco Jin Huk Choi Bruce Beutler |
| author_facet | Xue Zhong Nagesh Peddada Jianhui Wang James J. Moresco Xiaowei Zhan John M. Shelton Jeffrey A. SoRelle Katie Keller Danielle Renee Lazaro Eva Marie Y. Moresco Jin Huk Choi Bruce Beutler |
| author_sort | Xue Zhong |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-09T05:35:47Z |
| format | Article |
| id | doaj.art-9bb9af5e62a640e19549ec5330ca64ad |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T05:35:47Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-9bb9af5e62a640e19549ec5330ca64ad2023-12-03T12:29:16ZengNature PortfolioNature Communications2041-17232023-11-0114112210.1038/s41467-023-43456-zOVOL2 sustains postnatal thymic epithelial cell identityXue Zhong0Nagesh Peddada1Jianhui Wang2James J. Moresco3Xiaowei Zhan4John M. Shelton5Jeffrey A. SoRelle6Katie Keller7Danielle Renee Lazaro8Eva Marie Y. Moresco9Jin Huk Choi10Bruce Beutler11Center for the Genetics of Host Defense, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterIntermal Medicine-Histopathology Core, University of Texas Southwestern Medical CenterDepartment of Pathology, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterCenter for the Genetics of Host Defense, University of Texas Southwestern Medical CenterAbstract 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.https://doi.org/10.1038/s41467-023-43456-z |
| spellingShingle | Xue Zhong Nagesh Peddada Jianhui Wang James J. Moresco Xiaowei Zhan John M. Shelton Jeffrey A. SoRelle Katie Keller Danielle Renee Lazaro Eva Marie Y. Moresco Jin Huk Choi Bruce Beutler OVOL2 sustains postnatal thymic epithelial cell identity Nature Communications |
| title | OVOL2 sustains postnatal thymic epithelial cell identity |
| title_full | OVOL2 sustains postnatal thymic epithelial cell identity |
| title_fullStr | OVOL2 sustains postnatal thymic epithelial cell identity |
| title_full_unstemmed | OVOL2 sustains postnatal thymic epithelial cell identity |
| title_short | OVOL2 sustains postnatal thymic epithelial cell identity |
| title_sort | ovol2 sustains postnatal thymic epithelial cell identity |
| url | https://doi.org/10.1038/s41467-023-43456-z |
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