S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biomedical Sciences (대학원 의과학과) Theses (Ph.D. / Sc.D._의과학과)
Ctbp2 modulates chromatin states during embryonic stem cell differentiation
배아 줄기 세포의 분화 과정에서 Ctbp2에 의한 후생유전학적 조절 기전 연구
- 의과대학 의과학과
- Issue Date
- 서울대학교 의학대학원
- embryonic stem cells (ESCs); differentiation; core transcription factors (CTFs); C-terminal binding protein 2 (Ctbp2); nucleosome remodeling and deacetylation (NuRD); histone deacetylation; super-enhancer
- 학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의과학과 의과학전공, 2016. 2. 윤홍덕.
- The chromatin status is essential for cell fate determination. Accordingly, chromatin regulators are important for cell state transition process, such as deve1elopment and differentiation. Embryonic stem cells (ESCs) are maintained by core transcription factors (CTFs), which are closely connected with chromatin regulators to modulate chromatin environment and gene expression. The transcriptional corepressor C-terminal binding protein 2 (Ctbp2), which makes chromatin structures less accessible for transcription, is known as gating factor for pluripotency exit, but the underlying mechanism of Ctbp2 in ESC differentiation is poorly understood. Here, we show that Ctbp2 and ESC CTFs are co-occupied in active ESC genes and Ctbp2 mediates H3K27ac deacetylation in association with nucleosome remodeling and deacetylation (NuRD) complex during mouse embryonic stem cell (mESC) differentiation. In addition, it was confirmed that Ctbp2 occupies most of super-enhancers, regulatory region of CTFs. In undifferentiated conditions, knockdown of Ctbp2 causes aberrantly high H3K27ac level but the gene expression levels are not significantly changed. Even if differentiation signal is given, Ctbp2-knockdown cells fail to down-regulate ESC CTF expression, thereby sustaining ESC maintenance. The fact that Ctbp2 and NuRD complex preoccupy in super-enhancers accounts for the recent finding that super-enhancers are sensitive to perturbation. We validated above findings in human breast cancer cell line MCF7 by analyzing public genomewide ChIP-sequencing data, which shows that CTBP1/2 is associated with master transcription factors ERα, FOXA1, and GATA3 in ER positive breast cancer. Furthermore, CTBP1/2 is enriched in active chromatin regions, especially in most of super-enhancers. These suggest that CTBP1/2 is critical for not only mESC differentiation but also cancer differentiation and progression processes in human.