The Mechanism of Transcriptional Repression by Hairless

Hairless 的转录抑制机制

• 批准号: 6640569
• 负责人: GERARD MJ BEAUDOIN III
• 金额: $ 4.03万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6640569
• 关键词: DNA binding protein; gene induction /repression; nuclear receptors; nucleic acid sequence; predoctoral investigator; thyroid hormones; yeast two hybrid system

DESCRIPTION (provided by applicant): In humans, perinatal thyroid hormone (TH) deficiency results in developmental defects that in the nervous system includes mental retardation. TH acts through binding nuclear receptors (TR), which can control gene transcription. Thus, TH regulates development through induction of TH-responsive genes. hairless (hr) has been identified as a TH-responsive gene expressed in the brain, and thus is potentially involved in TH directed development of the nervous system.Our lab has recently defined the biochemical function of Hr as a corepressor that can act through TR. Corepressors are proteins that can repress transcription via a DNA bound transcription factor. Thus, the biochemical characterization of the protein has revealed that Hr may be involved in the mechanism of TR's transcriptional action. The purpose of the proposed research is to investigate the mechanism of Hr-based transcriptional repression, as this will lead to a greater understanding of how TR functions as a transcriptional regulator and how TR, through the recruitment of Hr, may affect nervous system development. I shall investigate Hr-based repression in three ways: 1) Determine the role of each of the repression domains in Hr-based repression; 2) Identify proteins that are recruited by Hr repression domains; 3) Demonstrate that the Hr-interacting protein is involved in Hr-based repression. By discerning the molecular mechanisms of Hr-mediated transcriptional repression, we may discover new avenues for therapeutic design to combat mental retardation as a consequence of altered gene expression.

描述（由申请人提供）：在人类中，围产期甲状腺激素（TH）缺乏导致神经系统发育缺陷，包括智力迟钝。TH通过结合核受体（TR）发挥作用，TR可以控制基因转录。因此，TH通过诱导TH应答基因来调节发育。无毛基因（hairless，hr）是一种在脑中表达的TH应答基因，可能参与TH介导的神经系统发育，本实验室最近将其生化功能确定为一种通过TR起作用的辅阻遏物。辅阻遏物是可以通过DNA结合的转录因子抑制转录的蛋白质。因此，该蛋白的生化特性表明，Hr可能参与TR的转录作用机制。这项研究的目的是研究基于Hr的转录抑制机制，因为这将有助于更好地了解TR如何作为转录调节因子发挥作用，以及TR如何通过招募Hr影响神经系统发育。我将从三个方面研究基于HR的阻遏：1）确定每个阻遏结构域在基于HR的阻遏中的作用; 2）鉴定由HR阻遏结构域招募的蛋白质; 3）证明HR相互作用蛋白参与基于HR的阻遏。通过识别HR介导的转录抑制的分子机制，我们可能会发现新的途径，治疗设计，以打击精神发育迟滞作为改变基因表达的结果。