BRG1によるクロマチン構造変化を介した細胞初期化促進メカニズムの解明

阐明BRG1介导的染色质结构变化促进细胞重编程的机制

• 批准号: 11F01388
• 负责人: 山中 伸弥
• 金额: $ 1.28万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11F01388/
• 关键词: Inducible Pluripotent Stem (iPS) cell; Reprogramming; Chromatin Remodeling; Epigenetic Regulation; Embryonic Stem (ES) cell; Regenerative Medicine; Induced Pluripotent Stem Cell(iPSC); Epigenetic Modification; Embryonic Stem Cell(ESC)

Induced pluripotent stem (iPS) cells can be generated from somatic cells by ectopic expression of four transcription factors : Oct4, Sox2, Klf4 and c-Myc. Examination of the start (fibroblasts) and end (iPSC) points, it is apparent that factor expression induces broad changes to the epigenome, yet how these changes are initiated and maintained during reprogramming remains largely unknown. Recent studies in ES cells showed that BRG1 is crucial for ES cell self-renewal and binding core ES cell genes. Further studies revealed that overexpression of BAF complex components BRGI and BAF155 enhanced cellular reprogramming, presumably by facilitating OCT4 binding to target gene promoters. I hypothesize that the chromatin remodeling activity of BRG1 is required in an early stage of iPS cell reprogramming, and may be equally critical at later stages of pluripotency maintenance.The main purpose of this research proposal is to shed light on the dynamic chromatin changes elicited by factor expression, highlighting the role of nucleosome remodeling through BRG1 as somatic cells transition to pluripotency.

诱导多能干 (iPS) 细胞可以通过四种转录因子的异位表达从体细胞产生：Oct4、Sox2、Klf4 和 c-Myc。通过检查起始点（成纤维细胞）和终止点（iPSC），很明显因子表达会引起表观基因组的广泛变化，但在重编程过程中如何启动和维持这些变化仍然很大程度上未知。最近对 ES 细胞的研究表明，BRG1 对于 ES 细胞的自我更新和结合核心 ES 细胞基因至关重要。进一步的研究表明，BAF 复合体成分 BRGI 和 BAF155 的过度表达可能通过促进 OCT4 与靶基因启动子结合来增强细胞重编程。我假设 BRG1 的染色质重塑活性在 iPS 细胞重编程的早期阶段是必需的，并且在多能性维持的后期阶段可能同样重要。本研究计划的主要目的是阐明由 BRG1 引起的动态染色质变化。因子表达，强调了当体细胞向多能性转变时通过 BRG1 进行核小体重塑的作用。