TRANSCRIPTIONAL INDUCTION BY THE HUMAN HMG 14 PROTEIN

细胞生长、分化和发育是由固定的 基因表达模式。 了解这些正常的细胞 和有机体进程的进展，以及他们的中断， 各种疾病状态，需要了解的调节， 在哺乳动物细胞中的转录。 所有的细胞基因都受到 在染色质背景下，长期以来人们一直认识到， 染色质在决定细胞的激活状态中起着核心作用， 一个基因 已知凝聚的染色质抑制细胞分裂的起始和 通过RNA聚合酶延长转录。 诱导基因 因此，表达通常需要将染色质重塑为 更扩展的配置，以便它变得可以访问， 特异性DNA结合蛋白和一般转录 机械. 引发和伸长都必须在 活性染色质状态，以便有效地表达基因。 最近，已经研究了特定的蛋白质或蛋白质复合物。 鉴定出具有改变染色质结构的能力。 在 特别是，我们和其他人已经表明，高度保守的 HMG-14/-17家族蛋白均能改变高阶染色质 结构化并通过RNA聚合酶II和III促进转录。 拟议的研究将调查生物化学和生物学 HMG-14激活转录的机制。一是 鉴定哪些染色质结构改变导致 HMG-14的转录诱导，通过确定是否 HMG-14转录激活区改变组蛋白H1染色质 相互作用或转录活性HMG-14的结合 改变核小体的构象或增强其移动性。 第二，HMG-14可能靶向特定基因的机制， 将通过确定HMG-14活动是否 受核心组蛋白乙酰化的影响，以及是否特异性相互作用 HMG-14与DNA结合转录因子的结合可能有助于 激活特定基因。 总之，这些研究应该定义 并描述了一种新的机制， 通过在特定基因处重组染色质结构来诱导。

Cell growth, differentiation, and development are driven by fixed patterns of gene expression. Understanding how these normal cellular and organismal processes progress, as well as their disruption in various disease states, requires knowledge of the regulation of transcription in mammalian cells. All cellular genes are regulated within a chromatin context, and it has long been appreciated that chromatin plays a central role in determining the activation state of a gene. Condensed chromatin is known to inhibit both the initiation and elongation of transcription by RNA polymerases. Induction of gene expression therefore often requires remodelling of the chromatin to a more extended configuration, so that it becomes accessible both to specific DNA-binding proteins and to the general transcription machinery. Both initiation and elongation must be facilitated in the active chromatin state in order to efficiently express a gene. Recently, specific proteins or complexes of proteins have been identified that have the capability to alter chromatin structure. In particular, we and others have shown that the highly conserved HMG-14/-17 family of proteins can both alter higher order chromatin structure and facilitate transcription by RNA polymerases II and III. The proposed studies will investigate the biochemical and biological mechanisms whereby HMG-14 activates transcription. First, we will identify which alterations in chromatin structure result in transcriptional induction by HMG-14, by determining whether the transcriptional activation region of HMG-14 alters histone H1-chromatin interactions or whether the binding of transcriptionally active HMG-14 changes the conformation or enhances the mobility of nucleosomes. Second, the mechanism by which HMG-14 may target specific genes for activation will be explored by determining whether HMG-14 activities are influenced by core histone acetylation, and whether specific interaction of HMG-14 with DNA-binding transcription factors may facilitate activation of particular genes. Together, these studies should define and characterize a novel mechanism for mediating transcriptional induction by reconfiguring the structure of chromatin at specific genes.