Functional Investigation of the Chromatin Remodeling Factor ZNHIT1 in the Maintenance of Homeostasis in the Mouse Thymus

FAN Shilin¹, LÜ Ke², WANG Yanli³, ZHU Sijie¹, Mathias Hochgerner², TANG Xiaofang^1,4*, LIN Xinhua^1,4*, WEI Wei^4,5*

(¹School of Life Sciences, Fudan University, Shanghai 200438, China; ²Institute of Human Phenome, Fudan University, Shanghai 200438, China;³Institutes of Biomedical Sciences, Inner Mongolia University, Hohhot 010070, China; ⁴Greater Bay Area Institute of Precision Medicine (Guangzhou), Guangzhou 511458, China; ⁵Department of Respiratory and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, China)

Abstract:

Thymus is the central organ for T cell development and the establishment of central tolerance. Its structure and function critically depend on the microenvironment provided by TEC (thymic epithelial cell). With aging, the thymus undergoes progressive involution, characterized by disorganized cortical-medullary architecture, adipose infiltration. Aging of the thymus leads to reduced immune function. Epigenetic dysregulation is recognized as a key driver of thymic involution. ZNHIT1 (zinc finger HIT domain-containing protein 1) is a core subunit of the SRCAP chromatin remodeling complex, mediating the deposition of the histone variant H2A.Z and influencing target gene transcription. However, its role in thymic homeostasis remains poorly defined. This study employed a mouse model with Znhit1 conditionally knocked out in TECs to systematically investigate the function of ZNHIT1 in maintaining thymic structure and function. Results demonstrated that ZNHIT1 deficiency in thymic epithelium led to significant thymic atrophy and disruption of cortical-medullary compartmentalization. Flow cytometric analysis revealed a reduction in total TEC numbers, an imbalance in the mTEC/cTEC value, and a marked decrease in the proportion of the stem-like MHCIIlo mTEC subpopulation. Mechanistically, ZNHIT1 ablation inhibited TEC proliferation and promoted apoptosis specifically in cTECs. This functional impairment of TECs subsequently disrupted T cell development, causing a block at the DN1 stage, a dramatic reduction in CD4+CD8+ DP (double-positive) thymocytes, and ultimately, insufficient output of naïve T cells to the periphery. Consequently, mice exhibited exacerbated inflammatory responses in a DNFB-induced contact hypersensitivity. Collectively, these findings establish that ZNHIT1 is essential for maintaining the TEC compartment and thymic microenvironment homeostasis. Its deficiency triggers thymic involution and leads to peripheral immune dysregulation. This work elucidates the role of a chromatin remodeler in regulating thymic homeostasis, providing novel mechanistic insights into the epigenetic underpinnings of thymic involution.

CSTR: 32200.14.cjcb.2026.07.0008