Pluripotent stem cells, such as ES cells and induced pluripotent stem cells (IPS cells) are important for their therapeutic potential in regenerative medicine, and it has been suggested that many transcription regulators are critical for their stemness (self-renewal and pluripotency) control. 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 process, however the molecular mechanisms of Myc in this process have not been addressed. Our recent work suggests that Myc has many interacting partner proteins in ES cells including co-factors in NuA4 histone acetyltransferase complex (NuA4 HAT complex). Previous studies showed that histone acetylation signature is involved in chromosome decondensation. Since the chromatin structure of ES cells is hyperdynamic and flexible compared to the chromosomal structure of differentiated cells, we propose that the function of Myc in ES cells or somatic cell reprogramming may be mediated by the interaction partner proteins of Myc including histone acetyltransferases. To further understand molecular mechanisms of Myc and its interacting partner proteins, I propose the following Specific Aims: 1) Identification of epigenetic signatures involved in the function ofthe Myc-centered network in ES cells. 2) Testing somatic cell reprogramming potential of each factor in Myc-centered regulatory network during IPS cell generation. :. The goals of this proposal are to understand the molecular mechanisms ofthe Myc-centered regulatory network in pluripotent stem cells and to develop alternative ways of efficient generation of iPS cells without oncogenic Myc.
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 understanding the roles of Myc in other research areas, such as cancer, and adult stem cells.
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|Beck, Samuel; Lee, Bum-Kyu; Rhee, Catherine et al. (2014) CpG island-mediated global gene regulatory modes in mouse embryonic stem cells. Nat Commun 5:5490|
|Rhee, Catherine; Lee, Bum-Kyu; Beck, Samuel et al. (2014) Arid3a is essential to execution of the first cell fate decision via direct embryonic and extraembryonic transcriptional regulation. Genes Dev 28:2219-32|