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The epigenetic modification in embryonic stem cell pluripotency : 후성유전학에 의한 줄기세포 전분화능 조절

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의과대학 의과학과
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서울대학교 대학원
ESCO-GlcNAcylationReprogrammingCtbp2PluripotencyCore transcription factorsPRC2Gene silencingiPSC
학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2014. 2. 윤홍덕.
Pluripotent stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are promising sources for regenerative medicine because of their ability to differentiate into all of the cell types in the body. In particular, iPSCs, which can be derived from patient tissue, have great potential to be used in patient- specific cell therapy. However, the practical application of such cells remains a distant goal due to our limited understanding of molecular mechanisms underlying pluripotency. Epigenetic modifications on chromatin are essential for appropriate cell state transition, such as developmental process, and uncontrolled these modifications give rise to disease. So, it is necessary to study epigenetic modifications in ESC pluripotency for regenerative medicine.
First, we investigated that the role of O-linked-N-acetylglucosamine (O-GlcNAc) in ESC maintenance and differentiation, and in somatic cell reprogramming. Because, O-GlcNAc has emerged as a critical regulator of diverse cellular processes, but its role in ESCs and pluripotency has not been investigated yet. Here we show that O-GlcNAcylation directly regulates core components of the pluripotency network. Blocking O-GlcNAcylation disrupts ESC self-renewal and reprogramming of somatic cells to iPSCs. The core reprogramming factors Oct4 and Sox2 are O-GlcNAcylated in ESCs, but the O-GlcNAc modification is rapidly removed upon differentiation. O-GlcNAc modification of Threonine 228 in Oct4 regulates Oct4 transcriptional activity and is important for inducing many pluripotency related genes, including Klf2, Klf5, Nr5a2, Tbx3 and Tcl1. A T228A point mutation that eliminates this O-GlcNAc modification reduces the capacity of Oct4 to maintain ESC self-renewal and reprogram somatic cells. Overall, our study makes a direct connection between O-GlcNAcylation of key regulatory transcription factors and the activity of the pluripotency network.
Second, we investigated the stable silencing of active ESC genes during differentiation. Pluripotency is governed by a core transcription factor (CTF) network to establish autoregulatory circuitry in ESCs. For proper exit from pluripotency to lineage commitments, CTF circuitry should be extinguished in an orderly manner by epigenetic regulation. Yet, how the stable silencing marker H3K27 trimethylation (H3K27me3) is recruited to active ESC genes during differentiation is poorly understood. Here we show that Ctbp2 is involved in Polycomb repressive complex 2 (PRC2)-mediated silencing of active ESC genes during differentiation. Ablation of Ctbp2 leads to inappropriate gene silencing in ESCs, thereby sustaining ESC maintenance during differentiation. Ctbp2 in ESCs associates with core components of PRC2 and Oct4. Ctbp2 regulates the recruitment of Ezh2 to active ESC genes and stimulates H3K27me3 during differentiation, which is pivotal for lineage commitment.
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