HMGA蛋白调控真核生物转录延伸过程的分子机制研究

High mobility group A (HMGA) proteins are the most abundant non-histones, DNA-binding chromatin factors in the eukaryotic nucleus. They do not display direct transcriptional activation capacity, but regulate gene expression via changing the DNA conformation by binding to AT-rich regions in the DNA and/or direct interaction with several transcription factors. These proteins are relatively abundant in pluripotent embryonic stem (ES) cells and most malignant human tumors, whereas they are undetectable in normal somatic cells. Only until recently, it has become increasingly clear that the elongation stage of eukaryotic transcription is a highly regulated process that it takes up the most time in generating full-length RNA transcripts.Therefore it is very important to elucidate the melocular mechanism that HMGA regulate sepecific gene transcription elongation in pluripotent embryonic stem (ES) cells and malignant human tumors. In this study, we will mainly focus on how HMGA interact with p-TEFB and other transcription elongation related proteins, such as FACT and IIS，furtherly change chromatin structrure and regultate transcription elongation in the embryonic stem cell line. Furthermore, using the chromatin assembly and chromatin transcription system in vitro, we will examine the roles of HMGA in the regulation of transcription initiation and elongation, respectively. Through this study, we are going to illuminate the melocular mechanisms how HMGA coordinates with other transcriptional elongation factors to regulate sepecific gene transcription elongation during the embryonic stem cells renewal and differentiation.

HMGA蛋白是一类非组蛋白染色质蛋白，它能通过与染色质结合而改变染色质的结构，或直接与转录调控相关蛋白发生作用，继而调节基因转录活性。HMGA在正常组织中低表达或者不表达，而在胚胎早期以及恶性肿瘤组织中的表达量非常高。真核基因转录延伸阶段是转录过程中耗时最长的阶段，也是基因转录调控最重要的环节。本项目主要研究HMGA通过与P-TEFB，FACT和SII等转录延伸相关蛋白及蛋白复合物相互作用，从而调控真核基因转录延伸过程，并进一步研究HMGA在胚胎干细胞自我更新和定向分化中的调控功能。同时，我们还将利用染色质体外转录分析平台，研究HMGA对基因转录活性的调控及其分子机理。通过本项目的研究，我们将从分子水平上揭示HMGA如何影响转录延伸因子的协同作用，阐明其在基因转录，特别是转录延伸调控中的作用，从而理解HMGA在胚胎干细胞自我更新和分化以及癌症的发生中的生物学功能及其分子机理。

真核基因转录延伸阶段是转录过程中耗时最长的阶段，也是基因转录调控最重要的环节。HMGA蛋白是一类非组蛋白染色质蛋白，它能通过与染色质结合而改变染色质的结构，或直接与转录调控相关蛋白发生作用，继而调节基因转录活性。HMGA在正常组织中低表达或者不表达，而在胚胎早期以及恶性肿瘤组织中的表达量非常高。在本项目的研究中，我们首次发现HMGA蛋白家族是7SKsn RNP蛋白复合物中的一种组成蛋白。HMGA可以通过调控p-TEFB 在7SKsnRNP蛋白复合体中的招募与释放来调控转录延伸过程。当在小鼠胚胎干细胞中敲除HMGA2，干细胞的早期发育分化标志物的表达受到了严重的影响，证明HMGA在胚胎干细胞的早期发育分化过程中起到了重要的作用。