A Myc-centered network in embryonic stem cells and somatic cell reprogramming

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DESCRIPTION (provided by applicant): My long-term career goal is to become an independent stem cell researcher pursuing further understanding of transcriptional regulatory mechanisms controlling self-renewal and differentiation in embryonic stem (ES) cells as well as induced pluripotent stem (iPS) cells. The 'Pathway to Independence Award (K99/R00)' will greatly support me to become a fully independent investigator by providing not only funding but also additional training opportunities. My immediate career goals during the mentored phase under the guidance of Dr. Stuart H. Orkin are first to expand my skills and knowledge to design and perform experiments addressing critical questions in stem cell research, and second, to broaden my interests in the field by communication with other researchers. The Children's Hospital Boston and Harvard Medical School provide a variety of training programs in addition to a unique research environment. The outstanding resources of these institutions will help me to accomplish my proposed research aims and allow me to have proper training during the mentored phase. Myc is one of the four transcription factors (Oct4, Sox2, Klf4, and Myc) used in generation of iPS cells and Is a protein of interest due to its dual roles In the reprogramming process; reactivation of Myc In the chimeric animals generated by iPS cells showed Increased tumorigenicity, but in the absence of Myc the efficiency of IPS cell generation was reduced by several hundred fold. These observations clearly imply the critical roles of Myc in facilitating direct reprogramming, however the molecular mechanisms of Myc In this process have not been addressed. Our preliminary studies suggest that Myc has many interacting partner proteins In ES cells including histone modifying enzymes. We propose that Myc promotes increased efficiency of reprogramming through the proteins with which it interacts. To understand molecular mechanisms of Myc and its interacting partner proteins, I propose the following Specific Alms: 1) Identification of the Myc-centered regulatory network in mouse ES cells. 2) Identification of epigenetic signatures involved in the function of the Myc-centered network. 3) Testing somatic cell reprogramming potential of each factor In Myc-centered regulatory network. The goals of this proposal are to understand the molecular mechanisms of the Myc-centered network and to develop alternative ways of efficient generation of IPS cells without oncogenic Myc. Relevance: The knowledge acquired from the proposed research will expand our understanding of a Myc-centered mechanism controlling pluripotency in ES cells, and somatic cell reprogramming process. This Information will facilitate development of patient-specific stem cell therapy by using ES cells and/or IPS cells. In addition, the data generated from this research will be a valuable resource for the understanding of roles of Myc in the other research areas, such as cancer, and adult stem cells.