Inflammatory cascades disrupt Treg function through epigenetic mechanisms

 描述（由申请人提供）：转录因子FOXP 3对调节许多使人衰弱的免疫介导的疾病至关重要。最近，已经描述了组蛋白甲基转移酶（HMT）EZH 2在FOXP 3的表观遗传调节和功能中的重要作用。炎症途径修饰EZH 2活性，并且炎症信号传导在体内和体外损害Treg功能。FOXP 3-EZH 2途径对IBD的生物学影响尚不清楚。我们的长期目标是剖析调节Treg细胞分化和功能的表观遗传机制，特别是在GI炎性疾病的背景下。这些发现将促进人类细胞治疗试验的设计， IBD。这项资助的目的是表征EZH 2在Treg抑制功能中的作用。 核心假设是EZH 2在Treg细胞的稳态中起关键作用，并且炎症信号传导途径对EZH 2功能的破坏有助于IBD。我们的基本原理是，在肠道炎症的背景下恢复Treg抑制功能的机制的鉴定将提供新的治疗机会。我们的具体目标将 测试以下假设：（Aim 1）FOXP 3对免疫调节基因网络的抑制需要在该转录因子和EZH 2之间形成复合物;（Aim 2）炎症刺激（如IL 6）导致EZH 2磷酸化，从而破坏该表观基因组调节因子的酶活性;（Aim 3）IL 6至EZH 2信号传导途径的抑制允许在肠道炎症背景下持续的Treg抑制功能。在结论中，我们将了解EZH 2在活动性炎症环境中Treg功能丧失中的作用。这一贡献是重要的，因为它将建立几个途径， 可用疗法（即IL 1 β、IL 6、TNFα）靶向的EZH 2 HMT具有通过翻译后修饰调节EZH 2 HMT活性的潜力。此外，目前的Treg细胞治疗试验虽然有希望，但尚未解决体内炎症诱导的Treg功能破坏的关键问题。这项研究具有创新性，因为我们研究了炎症信号通路对Treg细胞中表观遗传复合物的影响，这是一个迄今为止尚未研究过的过程。对表观遗传机制的深入了解是有影响的，因为T细胞祖细胞继承了亲本转录谱，并且与遗传变化不同，它们可以通过目前可用的疗法进行修饰。

 DESCRIPTION (provided by applicant): The transcription factor FOXP3 is critical to the regulation of numerous debilitating human immune-mediated diseases. Very recently, the essential role for the histone methyltransferase (HMT) EZH2 in the epigenetic regulation and function of FOXP3 has been described. Inflammatory pathways modify EZH2 activity, and inflammatory signaling impairs Treg function in vivo and in vitro. The biological impact of the FOXP3-EZH2 pathway to IBD is unknown. Our long-term goal is to dissect epigenetic mechanisms regulating Treg cellular differentiation and function, particularly within the setting o GI inflammatory diseases. These discoveries will facilitate design of human cell therapy trials for IBD. The objective of this grant is to characterize the role for EZH2 in Treg suppressive function. The central hypothesis is that EZH2 plays a critical role in the homeostasis of Treg cells, and the disruption of EZH2 function by inflammatory signaling pathways contributes to IBD. Our rationale is that identification of the mechanism(s) to restore Treg suppressive function in the setting of intestinal inflammation will offer new therapeutic opportunities. Our specific aims will test the following hypotheses: (Aim1) Repression of immunoregulatory gene networks by FOXP3 requires the formation of a complex between this transcription factor and EZH2; (Aim 2) Inflammatory stimuli, such as IL6 lead to EZH2 phosphorylation and thereby disrupt the enzymatic activity of this epigenomic regulator; (Aim 3) Inhibition of the IL6 to EZH2 signaling pathway permits sustained Treg suppressive function in the setting of intestinal inflammation. Upon conclusion, we will understand the role for EZH2 in Treg loss of function in the setting of active inflammation. This contribution is significant since it will establish that several pathways targeted by available therapies (ie IL1β, IL6, TNFα) have the potential to regulate EZH2 HMT activity through post- translational modifications. Furthermore, current Treg cell therapy trials, while promising have not addressed the key issue of in vivo inflammation-induced disruption of Treg function. The proposed research is innovative because we investigate the effect of inflammatory signaling pathways on epigenetic complexes in Treg cells, a heretofore-unexamined process. Insight into epigenetic mechanisms is impactful as T cell progenitor cells inherit the parent transcriptional profile and unlike genetic change, they are modifiable by currently available therapy.