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Dissecting transcriptional control by Klf4 in somatic cell reprogramming


Ectopic expression of four transcription factors, Oct4, Sox2, Klf4, and c-Myc, coverts somatic cells directly into induced pluripotent stem cells (iPSCs), which are functionally equivalent to embryonic stem cells (ESCs). The discovery of iPSC has been reshaping the methodology of disease modeling and drug screening in the past decade, and provides tremendous promise for regenerative medicine. However, the mechanism underlying this conversion process, reprogramming, is not yet fully understood. I aimed to dissect the reprogramming process, by characterizing the functional domains of one reprogramming factor Klf4. The transcriptional activation domain (TAD) of Klf4 was revealed to be critical for reprogramming. To search for the factors that mediates the functionality of Klf4 TAD, I identified transcriptional coactivators CBP/p300 and Mediator complex as the physical interaction partners of Klf4 TAD, and further showed that this interaction is functionally required for Klf4 mediated transcriptional activation in reprograming. Clathrin heavy chain, initially identified as a physical interaction partner of Klf4 TAD, was shown to be not required for Klf4 transcriptional activation. Clathrin heavy chain was furthered characterized for its potential transcriptional activation activity in CHC-TFE3, a chromosomal fusion discovered in renal cell carcinoma. Clathrin heavy chain, as a conventional vesicle coat protein involved cellular membrane trafficking, was further studied with its accessory protein Irc6 in budding yeast.

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