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STAT 5在控制多种CD 4 + T细胞谱系的发育中起关键作用， 包括调节性T细胞（T细胞）和T滤泡辅助细胞（TFH）。STAT 5通过启动和 抑制基因转录。然而，决定STAT 5是否结合的分子机制 导致基因转录或基因沉默的机制仍然是未知的。STAT 5已被证明与 共激活剂EP 300和CREBBP，这已被建议调节STAT 5功能;然而，共激活剂 在功能上调节STAT 5功能的阻遏物基本上仍不明确。同样不清楚的是， STAT 5：辅阻遏物复合物优先靶向STAT 5阻遏的基因，如果是这样， 这一机制解释了这种差异化的目标定位。因此，我们目前的知识的关键差距， STAT 5在T细胞中的功能包括：（i）鉴定生物学相关的STAT 5：辅阻遏物 影响T细胞发育的复合物，（ii）关于STAT 5：辅阻遏物复合物 影响T细胞中的基因表达，以及（iii）对STAT 5如何差异靶向共- 阻遏物复合物对STAT 5阻遏基因的作用。我们的初步数据有力地支持了 共阻遏物NCOR 1和NCOR 2在调节STAT 5依赖性T细胞分化中的作用。删除 Ncor 1或Ncor 2对T细胞发育的影响相对较轻。相反，Ncor 1和Ncor 2的缺失 对胸腺中的T细胞分化有显著影响。这些影响包括一个引人注目的块在 胸腺中FOXP 3+调节性T细胞的发育，以及T滤泡辅助细胞的明显增加， 派尔氏淋巴结。因此，T细胞中NCOR 1/2的缺失与STAT 5中观察到的几种表型相似。 敲除小鼠我们的总体假设是STAT 5与辅阻遏物NCOR 1的相互作用 和NCOR 2在T细胞发育中起关键作用。我们进一步提出STAT 5/NCOR复合物 通过序列特异性DNA结合位点靶向STAT 5抑制基因的独特子集，或 与其他转录因子的相互作用，也有助于招募NCOR辅阻遏物复合物。 这些目标的成功实现将为STAT 5改变基因表达的机制提供新的见解。 转录和染色质结构来促进T细胞分化。它还将提供基本的见解 转录因子选择性抑制特定基因转录的机制 而不阻断由相同转录因子诱导的其它基因的转录。