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

项目摘要 转录因子STAT5在调节多种CD4+T细胞系的发育中起着关键作用， 包括调节性T细胞(Tregs)和T滤泡辅助细胞(TFH)。STAT5通过启动和 抑制基因转录。然而，决定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仍是未知的。STAT5已经被证明可以与 共激活剂EP300和CREBBP被认为可以调节STAT5的功能；然而，共激活剂EP300和CREBBP被认为可以调节STAT5的功能。 在功能上调节STAT5功能的抑制子基本上仍然是未知的。同样不清楚的是， STAT5：共抑制物复合体优先针对受STAT5抑制的基因，如果是这样， 这一机制解释了这种不同的目标定位。因此，我们目前了解的主要差距是 STAT5在T细胞中的功能包括：(I)鉴定生物学上相关的STAT5：共抑制物 影响T细胞发育的复合体，(Ii)关于STAT5：共抑制物复合体如何 影响T细胞中的基因表达，以及(Iii)对STAT5如何不同地靶向辅助性基因的分子洞察。 STAT5抑制基因的抑制子复合体。我们的初步数据有力地支持了 共抑制基因NCOR1和NCOR2在调节STAT5依赖的T细胞分化中的作用删除任一项 NCOR1或NCor2对T细胞发育的影响相对较小。相反，NCOR1和NCor2都被删除 对胸腺中T细胞的分化有显著影响。这些撞击包括一个引人注目的障碍 胸腺中FOXP3+调节性T细胞的发育和T滤泡辅助细胞的明显增加 佩耶斯·帕茨。因此，T细胞中NCOR1/2的丢失与STAT5中观察到的几种表型相似 基因敲除老鼠。我们的主要假设是STAT5与共抑制物NCOR1相互作用 和NCOR2在T细胞发育中起关键作用。我们进一步提出了STAT5/NCoR复合体 通过序列特异的DNA结合位点或 与其他转录因子的相互作用也有助于招募NCoR共抑制物复合体。 这些目标的成功完成将为了解STAT5改变基因的机制提供深入的见解 转录和染色质结构促进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 而不会阻止由同一转录因子诱导的其他基因的转录。

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.