Co-repressors in STAT5-dependent CD4+ T Cell Development and Function

STAT5 依赖性 CD4 T 细胞发育和功能中的共阻遏物

• 批准号: 10614429
• 负责人: Michael Archibald Farrar
• 金额: $ 48.48万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614429
• 关键词: ATAC-seq; Affect; Binding; Binding Sites; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CREBBP gene; Cell Count; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; ChIP-seq; Chromatin Structure; Complex; Cre driver; DNA Binding; Data; Defect; Development; EP300 gene; Epigenetic Process; Exhibits; FOXP3 gene; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Grant; Helper-Inducer T-Lymphocyte; Histone Deacetylase; Knockout Mice; Knowledge; Mediating; Modification; Molecular; Mus; NCOR1 gene; NCOR2 gene; OX40; Peyer' s Patches; Phenotype; Play; Proteins; Regulation; Regulatory T-Lymphocyte; Repression; Role; Stat5 protein; T cell differentiation; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymocyte Development; Thymus Gland; gene repression; genetic corepressor; insight; loss of function; mutant; recruit; stem cells; thymocyte; transcription factor; transcriptome sequencing

Project Summary The transcription factor STAT5 plays key roles in governing the development of multiple CD4+ T cell lineages, including regulatory T cells (Tregs) and T follicular helper cells (TFH). STAT5 does this by both initiating and inhibiting gene transcription. However, the molecular mechanisms that determine whether STAT5 binding leads to gene transcription or gene silencing remain largely unknown. STAT5 has been shown to interact with the co-activators EP300 and CREBBP and this has been suggested to modulate STAT5 function; however, co- repressors that functionally modulate STAT5 function remain essentially undefined. Equally unclear is whether STAT5:co-repressor complexes are preferentially targeted to STAT5-repressed genes, and if so, what the mechanism is that accounts for this differential targeting. Thus, key gaps in our current knowledge of STAT5 function in T cells include: (i) identification of biologically relevant STAT5:co-repressor complexes that affect T cell development, (ii) information about how STAT5:co-repressor complexes affect gene expression in T cells, and (iii) molecular insights into how STAT5 differentially targets co- repressor complexes to STAT5-repressed genes. Our preliminary data strongly supports a key role for the co-repressors NCOR1 and NCOR2 in regulating STAT5-dependent T cell differentiation. Deletion of either Ncor1 or Ncor2 had relatively mild effects on T cell development. In contrast, deletion of both Ncor1 and Ncor2 had dramatic impacts on T cell differentiation in the thymus. These impacts included a striking block in the development of FOXP3+ regulatory T cells in the thymus, and a clear increase in T follicular helper cells in Peyers patches. Thus, loss of NCOR1/2 in T cells parallels several of the phenotypes observed in STAT5 knockout mice. Our overarching hypothesis is that STAT5 interactions with the co-repressors NCOR1 and NCOR2 play a critical role in T cell development. We further propose that STAT5/NCOR complexes are targeted to a unique subset of STAT5-repressed genes via sequence-specific DNA binding sites or interactions with other transcription factors that also help recruit NCOR co-repressor complexes. Successful completion of these aims will provide insights into the mechanism by which STAT5 alters gene transcription and chromatin structure to promote T cell differentiation. It will also provide fundamental insights into the mechanisms by which transcription factors can selectively repress transcription of specific genes without blocking transcription of other genes induced by that same transcription factor.

项目摘要 转录因子STAT5在管理多个CD4+ T细胞谱系的发展中起关键作用， 包括调节性T细胞（Tregs）和T卵泡辅助细胞（TFH）。 STAT5通过启动和 抑制基因转录。但是，确定STAT5结合的分子机制 导致基因转录或基因沉默在很大程度上未知。 STAT5已显示与 共激活器EP300和CREBBP，并建议调节STAT5功能。但是，共同 功能调节STAT5功能的阻遏物本质上仍然不确定。同样不清楚的是是否 STAT5：共抑制剂复合物优先针对STAT5抑制基因，如果是的，则是什么 机制是说明了这种差异靶向。因此，我们当前对 T细胞中的STAT5功能包括：（i）识别生物学相关的STAT5：共抑制剂 影响T细胞开发的复合物，（ii）有关STAT5：辅助剂复合物的信息 影响T细胞中的基因表达，以及（iii）分子见解STAT5如何差异化靶向靶向 抑制剂复合物对STAT5抑制基因。我们的初步数据强烈支持 共抑制剂NCOR1和NCOR2在调节STAT5依赖性T细胞分化方面。删除两个 NCOR1或NCOR2对T细胞的发育有相对温和的影响。相比之下，ncor1和ncor2的删除 对胸腺中T细胞分化产生了巨大影响。这些影响包括在 开发胸腺中Foxp3+调节性T细胞，并在T中明显增加T卵泡辅助细胞 Peyers补丁。因此，T细胞中NCOR1/2的丢失与STAT5中观察到的几种表型相似 淘汰老鼠。我们的总体假设是STAT5与共抑制器NCOR1的相互作用 NCOR2在T细胞开发中起关键作用。我们进一步提出了STAT5/NCOR复合物 通过序列特异性DNA结合位点或 与其他转录因子的相互作用也有助于募集NCOR共抑制复合物。 这些目标的成功完成将提供有关STAT5改变基因的机制的见解 转录和染色质结构以促进T细胞分化。它还将提供基本的见解 转录因子可以选择性地抑制特定基因的转录的机制 不阻止相同转录因子诱导的其他基因的转录。