학술/공연/행사

• 일시 : 2013.08.01

Induced pluripotent stem cells (iPSCs), which can be generated by ectopic expression of a set of defined embryonic stem cells (ESCs)-specific transcription factors, Pou5f1 (also known as Oct4), Sox2, Klf4 and c-Myc, are promising tools for disease models and patient-specific therapies. iPSCs functionally resemble ESCs in their capacity of self-renewal and differentiation. Despite the enormous promise for clinical applications, iPSC generation occurs with low efficiency, often with compromised pluripotency, suggesting the existence of a barrier(s) for the reprogramming and the induced pluripotency.To study the cellular and molecular barriers for somatic reprogramming, I characterized the functions of the miR-34 microRNAs (miRNAs) during reprogramming, since these miRNAs are bona fide targets of p53, one of the most important suppressors for somatic reprogramming. My previous study indicates that miR-34a is a key regulator of somatic reprogramming. During reprogramming, miR-34a is induced in a p53-depenent manner, and mediates part of the suppressive effect of p53 on reprogramming through post-transcriptional silencing of Sox2 and Nanog. Interestingly, ablation of miR-34a, unlike p53, results in a significant increase of reprogramming efficiency without compromising the pluripotency of iPSCs. The mammalian miR-34 miRNA family contains three homologues localized on two distinct genomic loci, miR-34a and miR-34b/c. My recent findings suggest that although the deficiency of either miR-34a or miR-34b/c enhances the reprogramming efficiency, miR-34b/c-/- iPSCs functionally more resemble wildtype ESCs and exhibit stronger pluripotency in vivo as compared to wildtype or miR-34a-/- iPSCs. It has been suggested that the compromised pluripotency observed in wildtype iPSCs can be partially attributed to the aberrant epigenetic regulation, as loss of imprinting of specific loci has been associated specifically with iPSCs, but not ESCs. My preliminary studies indicate that the p53-miR-34b/c axis plays an important role in promoting aberrant epigenetic silencing during reprogramming to suppress induced pluripotency. These results suggest that the role of the miR-34b/c miRNAs in regulating the pluripotency of iPSCs, and understanding the mechanisms underlying the epigenetic regulation of miR-34b/c during somatic reprogramming.