转录因子诱导细胞去分化和转分化重编程，是一个表观遗传修饰重建的过程，由转录因子结合到组织特异基因位点，引起染色体重塑和表观遗传改变，诱导组织特异基因表达。深入研究该过程表观遗传修饰重建和细胞对此的应答机制，对于理解分化细胞命运维持这一基本生物现象极为重要，对提高重编程效率也有应用价值。之前研究发现，p53的激活是去分化重编程的关键抑制机制。我们也发现失活p53的上游分子p19Arf，大大提高肝向转分化的效率。然而，对于p53是否应答了重编程过程的表观遗传修饰重建，以及激活p53的分子调控尚未明确。本项目将以成纤维细胞肝向转分化为研究体系，解析转录因子诱导的染色质重塑及表观遗传改变；阐明细胞应答染色质重塑和表观遗传改变的分子机制；着重揭示转分化重编程中染色质重塑是否激活p53，并鉴定关键调控蛋白。本项目将有助于深入理解细胞重编程的分子调控，也为高效获得iHep细胞提供理论支持。

Reprogramming induced by ectopic expression of transcription factors, such as dedifferentiation and transdifferentiation, is a process of epigenetic remodeling, including the binding of transcription factors, chromatin remodeling, epigenetic modification and tissue-specific gene expression. Dissecting the epigenetic remodeling and cellular responses during the whole process will not onlylead to novel insights into the understanding of the essential biological phenomenon, maintenance of cell identity, but also will help to improve the efficiency of reprogramming. Previous studies have revealed that p53 is a key barrier for induction of iPS cells during dedifferentiation. Our data have also showed that inactivation of p19Arf, an upstream regulator of p53, markedly increases efficiency of hepatic lineage conversion. However, it remains unclear whether p53 responds to epigenetic remodeling and by which mechanism p53 is activated. In this proposal, we would like to characterize the chromatin remodeling and epigenetic modification during hepatic lineage conversion and to identify the key mechanism responding to epigenetic remodeling. Specifically, we wish to address whether chromatin remodeling activates p53 and, if yes, which protein plays the key role linking chromatin remodeling and p53 activation. We expect that our findings would bring new ideas about cellular reprogramming as well as novel strategy to improve hepatic lineage conversion.