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

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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.