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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要转录因子 STAT5 在控制多种 CD4+ T 细胞谱系的发育中发挥着关键作用，包括调节性 T 细胞 (Treg) 和滤泡辅助 T 细胞 (TFH)。 STAT5 通过启动和抑制基因转录。然而，决定STAT5是否结合的分子机制导致基因转录或基因沉默的原因仍然很大程度上未知。 STAT5已被证明可以与共激活剂 EP300 和 CREBBP，这被认为可以调节 STAT5 功能；然而，共同功能性调节 STAT5 功能的阻遏蛋白基本上仍未定义。同样不清楚的是 STAT5：共抑制复合物优先靶向 STAT5 抑制基因，如果是这样，那么是什么机制是解释这种差异化目标的原因。因此，我们目前的知识中的关键差距 T 细胞中的 STAT5 功能包括： (i) 生物学相关 STAT5：辅阻遏物的鉴定影响 T 细胞发育的复合物，(ii) 有关 STAT5：共阻遏物复合物如何发挥作用的信息影响 T 细胞中的基因表达，以及 (iii) 对 STAT5 如何差异性靶向协同作用的分子见解 STAT5 抑制基因的阻遏复合物。我们的初步数据有力地支持了共阻遏物 NCOR1 和 NCOR2 调节 STAT5 依赖性 T 细胞分化。删除任一 Ncor1 或 Ncor2 对 T 细胞发育的影响相对较轻。相反，删除 Ncor1 和 Ncor2 对胸腺中 T 细胞的分化产生巨大影响。这些影响包括在胸腺中 FOXP3+ 调节性 T 细胞的发育，以及滤泡辅助 T 细胞的明显增加派耶斯斑块。因此，T 细胞中 NCOR1/2 的缺失与 STAT5 中观察到的几种表型相似基因敲除小鼠。我们的首要假设是 STAT5 与共阻遏物 NCOR1 相互作用 NCOR2 在 T 细胞发育中发挥着关键作用。我们进一步提出 STAT5/NCOR 复合物通过序列特异性 DNA 结合位点靶向 STAT5 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 共阻遏物复合物。成功完成这些目标将有助于深入了解 STAT5 改变基因的机制转录和染色质结构促进 T 细胞分化。它还将提供基本见解研究转录因子选择性抑制特定基因转录的机制而不阻断由同一转录因子诱导的其他基因的转录。