OVOL2 sustains postnatal thymic epithelial cell identity

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 () and Bruce Beutler ()
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Xue Zhong: University of Texas Southwestern Medical Center
Nagesh Peddada: University of Texas Southwestern Medical Center
Jianhui Wang: University of Texas Southwestern Medical Center
James J. Moresco: University of Texas Southwestern Medical Center
Xiaowei Zhan: University of Texas Southwestern Medical Center
John M. Shelton: University of Texas Southwestern Medical Center
Jeffrey A. SoRelle: University of Texas Southwestern Medical Center
Katie Keller: University of Texas Southwestern Medical Center
Danielle Renee Lazaro: University of Texas Southwestern Medical Center
Eva Marie Y. Moresco: University of Texas Southwestern Medical Center
Jin Huk Choi: University of Texas Southwestern Medical Center
Bruce Beutler: University of Texas Southwestern Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43456-z

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