Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, 75390-8505, USA.
Department of Population and Data Sciences, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390-8821, USA.
Nat Commun. 2023 Nov 27;14(1):7786. doi: 10.1038/s41467-023-43456-z.
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.
不同的途径和分子可能支持胚胎期和出生后胸腺上皮细胞（TEC）的发育和维持。在这里，我们确定了一种维持出生后 TEC 数量和功能的机制。OVOL2 的一个有活力的错义等位基因（C120Y），在 TEC 中广泛或特异性表达，导致淋巴细胞减少症，其中 T 细胞发育因皮质 TEC 功能障碍和皮质 TEC 丧失而受损。我们表明，在 OVOL2 缺陷小鼠中，TEC 的上皮特性异常地向间充质状态转变。我们证明 OVOL2 抑制表观遗传调节 BRAF-HDAC 复合物，特异性破坏 RCOR1-LSD1 相互作用。这导致 LSD1 介导的 H3K4me2 去甲基化的抑制，导致染色质可及性和上皮基因的转录激活。因此，OVOL2 控制 TEC 的表观遗传景观以维持 TEC 特性。非冗余的 TEC 维持的出生后机制的鉴定为理解胸腺萎缩提供了一个切入点，胸腺萎缩通常在成年早期开始。
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