Scientist Institute of Molecular and Cell Biology (IMCB), Singapore
Abstract: Despite extensive study of gene regulation in mouse embryonic stem cells, the role of 3D genomic interactions and transposable elements (TEs) in pluripotent state-specific gene expression remains unclear. Understanding this is crucial for fully harnessing the differentiation potential of each state. Here, we investigate how TE-derived enhancer interactions differ between the conventional naïve state and the expanded state with extraembryonic differentiation capacity. Using integrative HiC, ChIP, and H3K27ac HiChIP analyses, we identified mammalian-wide interspersed repeat (MIR), a short interspersed nuclear element (SINE) family member, as highly associated with naïve-specific genomic interactions. In the naïve state, Esrrb co-opts MIR enhancers to regulate the naïve-specific gene expression program, forming enhancer and super-enhancer loops. We demonstrated that the loss of an Esrrb-bound MIR enhancer impairs self-renewal, underscoring its importance. Additionally, Esrrb co-binds with Yy1, a structural protein complex, at MIR enhancers, highlighting its topological role. Altogether, our study reveals the significance of Esrrb at MIR-derived enhancers in shaping the naïve potency state. This finding advances the recognition of TEs as an element of gene regulation.
