染色质重塑因子Znhit1在肺发育中的作用及其机制

Chromatin remodeling induced by the changing of nucleosome components is an important form of epigenetic regulation. It is known that the chromatin remodeling complex SRCAP could mediate the replacement of Histone H2A in the nucleosome by the histone variant H2A.Z, but the role of chromatin remodeling in organ development and tissue homeostasis in mammals is still unclear. In our previous work, we knocked out Znhit1, a key subunit of the SRCAP complex, in the mouse endodermal epithelium, and found that the deletion of the Znhit1 resulted in lung development defects in mice as manifested by abnormal pulmonary branching morphogenesis, distal branch expansion and mesenchymal tissue development disorder. On the basis of our preliminary study, this project will elaborate the function of Znhit1 in the regulation of the development of lung epithelial cells and provide insights into the mechanism of "epithelial-mesenchymal" interaction that affect lung morphogenesis. The expected results will comprehensively deepen our understanding of the fate determination and the development of lung epithelial cells. This study will also provide an important theoretical basis for in-depth understanding of development-related lung diseases and potential intervention target mining.

核小体组分变化引发的染色质重塑，是表观遗传调控基因时序表达的重要形式。已知，染色质重塑复合物SRCAP可主动介导组蛋白变异体H2A.Z对核小体中组蛋白H2A的替换，但染色质重塑在哺乳动物器官发育与组织稳态中的作用并不清楚。申请人通过在小鼠内胚层上皮中特异性敲除SRCAP复合体关键亚基Znhit1，发现其缺失导致小鼠肺发育缺陷：肺分枝形态发生异常、分枝末端膨胀和间质发育障碍。此项目将在此基础上，详细阐述Znhit1在肺上皮细胞发育过程中的作用及分子机制，并揭示“上皮-间质”相互作用影响肺形态发生的机理。预期成果将全面加深我们对肺上皮细胞命运决定和发育过程的理解，并为干预肺发育相关疾病提供重要理论基础和潜在靶点。

目前对于肺的发育缺陷与再生障碍缺乏深入的系统性研究。尽管已经发现了诸多转录因子与形态发生素等参与调控肺发育或再生，关于表观遗传相关的DNA甲基化与组蛋白修饰已有较多研究，但有关组蛋白变异体的研究仍留有许多空白。组蛋白变异体是如何影响肺损伤后的再生修复，尚不清楚。研究团队前期工作证实Znhit1作为介导H2A.Z整合的重要亚基，参与调控H2A.Z在哺乳动物成体干细胞命运决定与稳态维持中的作用，为后续工作的开展提供了突破口。.本研究利用Znhit1条件敲除小鼠，通过Shh-Cre工具鼠分别得到发育期肺上皮细胞中的Znhit1缺陷型小鼠。同时通过3D类器官培养，研究团队首次对Znhit1在哺乳动物肺发育与再生修复中的作用机制展开研究。本研究的开展有助于加深对表观遗传因子参与肺形态发育与损伤后再生中关键信号调控等问题的理解，同时建立更为成熟的肺泡类器官体系，为肺相关疾病的诊断和治疗提供重要的理论与技术基础。