固有淋巴样细胞（ILC）是近来发现的一群天然免疫淋巴细胞，在粘膜免疫和稳态维持中发挥重要作用。染色质重塑复合物通过调控基因表达参与生命过程的调控，然而表观遗传调控ILC谱系建立及功能机制尚不明了。申请人前期发现，TIP60重塑复合物重要亚基Yeats4在ILC1、ILC2、ILC3及其前体细胞αLP中高表达，Yeats4敲除小鼠小肠中ILC1、ILC2和ILC3数量和比例显著降低。还发现，发现Yeats4主要调控αLP向下游谱系的发育分化，最终导致ILC1、ILC2和ILC3的数目减少。我们初步证实Yeats4能够与Dot1l蛋白相互作用，富集在Lmo4启动子区域，并促进Lmo4基因的表达。在此基础上，本课题将利用Yeats4和Lmo4等多种遗传敲除小鼠工具，综合使用ILC体内外分化及骨髓移植体系，深入探讨Yeats4通过调节Lmo4基因的表达而调控ILC细胞发育分化的分子机制。

Innate lymphoid cells (ILCs) are a group of recently identified natural immune lymphocytes, which play an important role in mucosal immunity and homeostatic maintenance. Chromatin remodeling complexes are involved in the regulation of life processes through modulating gene expression. However, The mechanism that epigenetic modulation regulates ILC development and function remains unknown. In previous work, the applicant found that Yeats4, an essential subunit of TIP60 complex, is highly expressed in ILC1, ILC2, ILC3 and αLP precursor cells. And Yeats4 deficiency results in decreased the numbers and proportions of ILC1, ILC2 and ILC3 in small intestine. In vivo differentiation assays and bone marrow transplantation experiments indicated Yeats4-deficient αLP cells generate less ILC1, ILC2 and ILC3. Our preliminary data showed that Yeats4 interacts with Dot1l, enriches in Lmo4 promoter, and promotes Lmo4 expression. On this basis, we will exploit mutiple genetic knockout mouse tools and bone marrow transplantation system to investigate the molecular mechanism that Yeats4 regulates Lmo4 expresson to initiate ILC development and differentiation.