Epigenetic and 3D chromatin landscape modulation from pluripotent to expanded-potential stem cells

• Main Author: Zeng, Yingying
• Other Authors: Peter Droge
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2023
• Subjects: Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/165360
• Institution: Nanyang Technological University

The mechanisms underlying the gene regulation and enhancer-promoter rewiring which contribute to the transition of mouse embryonic stem cells (ESC) to totipotent-like expanded-potential stem cells (EPSCs) are still unknown. To obtain a comprehensive understanding of the totipotency, I show the extensive changes in transcriptome, epigenome, and 3D chromatin structure in EPSC compared to ESC using integrative analyses. Through the differential accessibility and histone marks analysis, the potential regulators related to the chromatin state changes in EPSC were identified. Using HiC analysis, detailed maps of enhancer-promoter interactions were generated, and EPSC-specific genomic interactions were found to be associated with the differentially expressed genes in EPSC compared to ESC. Transposable elements (TEs) are not merely junk DNA regions, instead, they were found to play pivotal roles in regulating gene transcription and chromatin architecture. In a pursuit to deepen our understanding of their roles in pluripotency or expanded-potency, I found that mammalian-wide interspersed repeats (MIRs) were significantly enriched with the motif of a nuclear receptor factor and in the enhancer regions, which suggested that MIRs may provide binding sites for the nuclear receptor factor in ESC and help to mediate the chromatin interactions between enhancers and promoters in ESC. While in EPSC, I could see the inactivation of a subset of ESC-active enhancers, accompanied by a reduction of nuclear receptor factor binding and its mediated chromatin loops, especially the interactions around those MIR-enhancers. According to these findings, this nuclear receptor factor and MIR work cooperatively to maintain pluripotent ESCs, and they play different regulatory roles in EPSCs.