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Title: Screen of Nuclear Receptors for the Enhanced and Alternative Generation of Induced Pluripotent Stem Cells
Keywords: induced pluripotent stem cell, reprogramming, nuclear receptor, embryonic stem cell, transcripion factor, Nr5a2
Issue Date: 28-Dec-2011
Source: DOMINIC HENG JIAN CHIEN (2011-12-28). Screen of Nuclear Receptors for the Enhanced and Alternative Generation of Induced Pluripotent Stem Cells. ScholarBank@NUS Repository.
Abstract: Differentiated cells are typified by their lineage restriction. Nevertheless, a pluripotent state of unrestricted multilineage differentiation potential may be experimentally endowed upon differentiated cells via the process of pluripotential reprogramming in which the lineage restriction of differentiated cells is undone. The resultant cells, known colloquially as induced pluripotent stem cells (iPSCs), become akin to pluripotent embryonic stem cells (ESCs) and pluripotent cells of the early embryo, thus gaining their characteristic developmental potential and other characteristics diagnostic of pluripotent cells. Conferral of pluripotency upon differentiated cells is achieved by overexpressing pluripotency-associated transcription factors in these cells, such as Oct4, Sox2, Klf4, and c-Myc. Here, I have investigated whether a heretofore underappreciated class of transcription factors, known as nuclear receptors, can function similarly to conventional pluripotency transcription factors to reprogram mouse fibroblasts into iPSCs. I have identified two nuclear receptors, Nrli2 and Nr5a2, that can enhance the efficiency of iPSC generation by about 3- to 4-fold, respectively. Saliently, Nr5a2 can fully replace the need for exogenous Oct4 to generate mouse iPSCs, making it the first known factor capable of ¿replacing¿ Oct4 in iPSC reprogramming. Its close family member Nr5a1 functions similarly in substituting for Oct4. Piqued by how Nr5a2 can replace the singularly important Oct4 in iPSC generation, I have furthermore found that Nr5a2 is endogenously required for iPSC generation¿bereft of it, few iPSCs form. Moreover, in reprogramming fibroblasts, Nr5a2 directly binds the Nanog enhancer and upregulates expression of the dominant pluripotency factor Nanog. In brief, my study illuminates an unexpected role for nuclear receptors in iPSC generation, identifies Nr5a2 as the first factor that can functionally substitute for Oct4 in iPSC reprogramming (formerly thought indispensible), and sheds light on the mechanism of action of Nr5a2.
Appears in Collections:Ph.D Theses (Open)

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