S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biomedical Sciences (대학원 의과학과) Theses (Ph.D. / Sc.D._의과학과)
The regulatory role of Ctbp2-interacting zinc finger proteins, Zfp217 and Zfp516, in embryonic stem cell differentiation
Ctbp2와 결합하는 zinc finger protein, Zfp217과 Zfp516에 의한 배아줄기세포 분화 조절
- 의과대학 의과학과
- Issue Date
- 서울대학교 대학원
- C-terminal binding protein 2 (Ctbp2); Zinc finger protein 217 (Zfp217); Zinc finger protein 516 (Zfp516); embryonic stem cells; chromatin regulators; exit from pluripotency
- 학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의과학과, 2018. 2. 윤홍덕.
- Transcription factors and chromatin remodeling proteins control the transcriptional variability for embryonic stem cell (ESC) lineage commitment. During ESC differentiation, chromatin modifiers are recruited to the regulatory regions by transcription factors, thereby activating the lineage-specific genes or silencing active ESC genes. On differentiation cue, active ESC genes are silenced by C-terminal binding protein 2 (Ctbp2) and its binding complexes, the nucleosome remodeling and deacetylation (NuRD) complex and the polycomb repressive complex 2 (PRC2), which each modify H3K27 deacetylation and tri-methylation mediated repression. However, Ctbp2 itself is unable to bind to the DNA, which leaves a missing link in Ctbp2-mediated epigenetic regulation during stem cell differentiation. Also, the underlying mechanisms that link transcription factors to the exit from pluripotency are not yet identified. Thus, it is necessary to search for transcription factors that fine-tune Ctbp2 and these epigenetic regulators on active ESC genes. In this study, we analyzed the role of the Ctbp2-interacting zinc finger proteins, Zfp217 and Zfp516, as linkers for the chromatin regulators during ESC differentiation. CRISPR-Cas9-mediated double knock-outs of both Zfp217 and Zfp516 in ESCs prevented the exit from pluripotency. Both zinc finger proteins cooperatively regulated the Ctbp2-mediated NuRD complex and PRC2 complex recruitment to active ESC genes, subsequently switching the H3K27ac to H3K27me3 during ESC differentiation. Therefore, we suggest that zinc finger proteins, Zfp217 and Zfp516, orchestrate with Ctbp2 to control the concise epigenetic states on active ESC genes during differentiation, resulting in natural lineage commitment.