S-Space Graduate School of Convergence Science and Technology (융합과학기술대학원) Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과) Theses (Ph.D. / Sc.D._분자의학 및 바이오제약학과)
Dynamic higher-order chromatin structure mediated by cohesin complex contributes to tumor development
- 융합과학기술대학원 분자의학 및 바이오제약학과
- Issue Date
- 서울대학교 융합과학기술대학원
- Cohesin; higher-order chromatin structure; gene amplification; epithelial-mesenchymal transition; cancer stem cell; cancer metastasis
- 학위논문 (박사)-- 서울대학교 융합과학기술대학원 : 바이오제약학과, 2016. 8. 김태유.
- Higher-order chromatin architecture is known to be important to gene regulation during hematopoiesis, erythropoiesis, and development. Chromatin architectural molecule cohesin complex tightly and dynamically controls genomic organization to regulate transcript splicing, gene transcription, and chromosomal instability in cancer. Although substantial evidences have shown that cohesin complex is involved in tumorigenesis, the effects of chromatin architecture-mediated by cohesin complex on tumor development are still unclear.
Here, we show that 1) highly amplified genes form typical long-range chromatin interactions, which are stabilized by enriched cohesin. Impaired cohesin complex inhibits DNA replication initiation by reducing the recruitment of pre-replication complexes such as minichromosome maintenance subunits 7 (MCM7), DNA polymerase α, and CDC45 at replication origins near the amplified regions, and as a result, decreases the DNA copy numbers of highly amplified genes. Collectively, our data demonstrate that cohesin-mediated chromatin organization and DNA replication are important for stabilizing gene amplification in cancer cells with chromosomal instability.
Next, 2) we report that cohesin-mediated chromatin organization initiates and coordinates EMT by activating mesenchymal genes. Depletion of RAD21 in epithelial cancer cells causes transcriptional activation of TGFB1 and ITGA5, inducing EMT. Reduced binding of RAD21 changes intrachromosomal chromatin interactions within the TGFB1 and ITGA5 loci, creating an active transcriptional environment. Similarly, stem cell-like cancer cells also show an open chromatin structure at both genes, which correlates with high expression levels and mesenchymal fate characteristics. These findings indicate that dynamic cohesin-mediated chromatin structures are responsible for the initiation and regulation of essential EMT-related cell fate changes in cancer.