HIC1调控CIITA转录机制研究及其在B细胞分化中的意义

项目名称： HIC1调控CIITA转录机制研究及其在B细胞分化中的意义

项目编号： No.31270805

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 徐涌

作者单位： 南京医科大学

项目金额： 80万元

中文摘要： 依赖于MHC II的抗原呈递是启动适应性免疫反应的必要步骤。在成熟的B细胞中，CIITA是决定MHC II转录激活的关键调控因子。在B细胞分化为浆细胞过程中，CIITA的表达在转录水平被抑制，从而导致MHC II水平下调。这一过程是B细胞分化的标志性事件，但其中的分子机制尚未阐明。B细胞分化异常在临床上导致B细胞淋巴瘤。我们前期的研究发现，转录抑制因子HIC1可以结合到CIITA的启动子上并抑制CIITA的转录。进一步的研究发现，HIC1的表达在B细胞分化过程中上调。因此，我们提出一个假说，即刺激B细胞分化的因素通过激活HIC1引起CIITA表达的沉默，最终实现从B细胞向浆细胞的分化。我们拟从1）HIC1介导CIITA转录抑制的机制和2）B细胞分化过程中HIC1表达上调的机制这两个方面来研究HIC1促使B细胞分化的机制，并为临床预防或治疗B细胞淋巴瘤提供有价值的线索。

中文关键词： 转录调控；表观遗传学；B细胞分化；DNA甲基转移酶；

英文摘要： Major histocompatibility complex II (MHC II) dependent antigen presentation links CD4+ T cell activation to the initiation of adaptive immunity. In mature B lymphocytes, class II transactivator (CIITA) is the master regulator of MHC II transcription. During the transition from B cell to plasma cell, CIITA expression itself is transcriptionally silenced, which results in the loss of MHC II expression. This process constitutes a hallmark event during B cell differentiation and aberrant differentiation is associated B cell malignancy; the underlying mechanism, however, remains incompletely understood. Our preliminary data suggest that the transcriptional repressor HIC1 binds to the proximal promoter of CIITA and represses its transcription. In addition, HIC1 message levels are up-regulated during B cell differentiation. Therefore, we hypothesize that factors that drive B cell differentiation promote CIITA repression via activating HIC1. Our specific aims are to 1) unveil the mechanism whereby HIC1 represses CIITA transcription during B cell differentiation, and 2) the mechanism whereby HIC1 transcription is up-regulated during B cell differentiation. Our ultimate goal is to clarify the regulatory circuit that connects CIITA repression to B cell differentiation and to provide critical insights into the intervention

英文关键词： transcriptional regulation；epigenetics；B cell differentiation；DNMT；