TRANSCRIPTIONAL INDUCTION BY THE HUMAN HMG 14 PROTEIN

人 HMG 14 蛋白的转录诱导

• 批准号: 2471334
• 负责人: ULLA M HANSEN
• 金额: $ 26.94万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2471334
• 关键词: acetylation; autoradiography; chromatin; complementary DNA; gene induction /repression; genetic transcription; histones; nucleoproteins; nucleosomes; protein binding; protein structure function; transcription factor

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.

细胞的生长、分化和发育是由固定的驱动力驱动的 基因表达模式。 了解这些正常细胞如何 和有机过程的进步，以及它们对 不同的疾病状态，需要了解调节的知识 哺乳动物细胞中的转录。 所有细胞基因均受到调控 在染色质背景下，人们很早就认识到 染色质在决定染色质的激活状态中起着核心作用 一个基因。 已知浓缩染色质可抑制起始和 RNA聚合酶的转录延伸。 基因诱导 因此，表达通常需要将染色质重塑为 更多扩展配置，以便两者都可以访问 特定 DNA 结合蛋白和一般转录 机械。 必须促进引发和延伸 活跃的染色质状态，以便有效地表达基因。 最近，特定蛋白质或蛋白质复合物已被 鉴定出具有改变染色质结构的能力。 在 特别是，我们和其他人已经证明，高度保守的 HMG-14/-17 蛋白家族均可改变高级染色质 结构并促进 RNA 聚合酶 II 和 III 的转录。 拟议的研究将调查生物化学和生物 HMG-14 激活转录的机制。首先，我们将 确定染色质结构的哪些改变导致 HMG-14 的转录诱导，通过确定是否 HMG-14 的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 的结合是否 改变核小体的构象或增强核小体的流动性。 其次，HMG-14可能靶向特定基因的机制 将通过确定 HMG-14 活性是否 受核心组蛋白乙酰化的影响，以及是否存在特异性相互作用 HMG-14 与 DNA 结合转录因子的结合可能会促进 特定基因的激活。 这些研究共同应该定义 并描述了介导转录的新机制 通过在特定基因处重新配置染色质结构来诱导。