Repression of the hTERT gene during cell differentiation

细胞分化过程中 hTERT 基因的抑制

• 批准号: 6916309
• 负责人: JIYUE ZHU
• 金额: $ 25.95万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6916309
• 关键词: DNA binding protein; DNA footprinting; cell differentiation; cell line; chemical structure function; chromatin; chromatin immunoprecipitation; gene induction /repression; genetic regulatory element; genetic transcription; histones; posttranslational modifications; telomerase

DESCRIPTION (provided by applicant): Our long-term goal is to understand the critical steps of hTERT gene regulation during development. The hTERT gene, which encodes the rate-limiting subunit of human telomerase, is expressed at a high level in embryonic tissues and stem cells, but is repressed upon differentiation in the majority of adult somatic cells. Although the hTERT promoter has been studied extensively, the contribution of chromatin environment and the requirement of cis-elements have not been determined for the repression of the endogenous hTERT transcription. Previous results, including our own, have indicated that native chromatin plays a critical role in the regulation of hTERT transcription. hTERT transcription can be reversibly induced by inhibition of histone deacetylases and this induction is accompanied by chromatin remodeling at the hTERT promoter. Furthermore, we and others have shown that transiently transfected plasmid reporters are not ideal models for the repression of endogenous hTERT gene in somatic cells. Based on these findings, we hypothesize that chromatin environment is a critical component of the regulatory mechanisms for the repression of the native hTERT promoter. Here, we plan to study the molecular details of hTERT repression in a chromatin context using TPA-induced U937 cell differentiation as a model. We propose to pursue three interconnected aims: (1) To determine the role of global chromatin environment in hTERT repression during differentiation; (2) To determine sequential events of nuclear factor recruitment and histone modifications that occur at the hTERT core promoter region during differentiation. (3) To create a novel chromosome-based reporter system and dissect the roles of cis-regulatory elements in hTERT repression.

描述（由申请人提供）：我们的长期目标是了解hTERT基因在开发过程中的关键调控步骤。hTERT基因编码人类端粒酶的限速亚基，在胚胎组织和干细胞中高水平表达，但在大多数成年体细胞分化时受到抑制。虽然hTERT启动子已被广泛研究，但染色质环境的贡献和顺式元件的需求对内源性hTERT转录的抑制作用尚未确定。