Dissecting the establishment and regulation of human pluripotency

描述（由申请人提供）：诱导多能干细胞（iPS）在促进我们对人类发育和疾病的理解方面具有巨大的潜力。为了帮助释放这一潜力，我们组织了一个项目来(a)全面识别维持细胞多能状态的调控网络的遗传和表观遗传成分；(B)描述多能细胞中这些成分活性在培养诱导下的变化；(C)描述了它们在多能性诱导过程中活性的时间变化。为了实现这些目标，我们制定了四个相互依存的项目：

DESCRIPTION (provided by applicant): Induced pluripotent stem (iPS) cells have a tremendous potential for aidvancing our understanding of human development and disease. To help unlock this potential we have organized a program to (A) comprehensively identify the genetic and epigenetic components of the regulatory network that maintains cells in a pluripotent state; (B) characterize culture-induced variation in the activites of these components in pluripotent cells; and (C) characterize temporal variation in their activities during induction of pluripotency with defined factors. To achieve these goals, we have formulated four interdependent projects: Project I (Meissner) will (1) characterize transcriptional coregulators and small non-coding RNAs that modulate the activity of the core pluripotency transcription factors, and (2) define and isolate subpopulations from pluripotent cell cultures to characterize their transcriptional and epigenetic states. Project II (Rinn) will characterize long non-coding RNAs expressed in pluripotent cells and elucidate their role in remodeling the epigenetic landscape during reprogramming. Project III (Mikkelsen) will characterize the cis-regulatory modules that direct activation, maintenace and repression of gene expression in pluripotent cells by recruiting transcription factors and their coregulators to key genomic loci. Project IV (Eggan) will characterize the inheritance patterns and maintenance of inactivated X chromosomes during reprogramming and in pluripotent cell cultures. The four projects rely on complementary use of innovative high-throughput genomic and proteomic technologies to profile high-quality iPS cell lines. The integration of data and insights from each of the projects will generate a comprehensive view of protein-protein, protein-RNA and protein-DNA interactions essential to the maintenace of pluripotency (goal A). This intergrated view will then guide studies of culture- induced and temporal variation in the network (goals B and C).