Rewiring of SINE-MIR enhancer topology and Esrrb modulation in expanded and naive pluripotency

Rewiring of SINE-MIR enhancer topology and Esrrb modulation in expanded and naive pluripotency

Abstract Background The interplay between 3D genomic structure and transposable elements (TE) in regulating cell state-specific gene expression program is largely unknown. Here, we explore the utilization of TE-derived enhancers in naïve and expanded pluripotent states by integrative analysis of gen...

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Main Authors: Nadia Omega Cipta, Yingying Zeng, Ka Wai Wong, Zi Hao Zheng, Yao Yi, Tushar Warrier, Jian Zhou Teo, Jia Hao Jackie Teo, Yee Jiun Kok, Xuezhi Bi, Reshma Taneja, Derrick Sek Tong Ong, Jian Xu, Florent Ginhoux, Hu Li, Yih-Cherng Liou, Yuin-Han Loh
Format: Article
Language:English
Published: BMC 2025-04-01
Series:Genome Biology
Subjects:
3D genome
Pluripotency
Transposable element
Mouse embryonic stem cells
Online Access:https://doi.org/10.1186/s13059-025-03577-8
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Summary:Abstract Background The interplay between 3D genomic structure and transposable elements (TE) in regulating cell state-specific gene expression program is largely unknown. Here, we explore the utilization of TE-derived enhancers in naïve and expanded pluripotent states by integrative analysis of genome-wide Hi-C-defined enhancer interactions, H3K27ac HiChIP profiling and CRISPR-guided TE proteomics landscape. Results We find that short interspersed nuclear elements (SINEs) are the more involved TEs in the active chromatin and 3D genome architecture. In particular, mammalian-wide interspersed repeat (MIR), a SINE family member, is highly associated with naïve-specific genomic interactions compared to the expanded state. Primarily, in the naïve pluripotent state, MIR enhancer is co-opted by ESRRB for naïve-specific gene expression program. This ESRRB and MIR enhancer interaction is crucial for the formation of loops that build a network of enhancers and super-enhancers regulating pluripotency genes. We demonstrate that loss of a ESRRB-bound MIR enhancer impairs self-renewal. We also find that MIR is co-bound by structural protein complex, ESRRB-YY1, in the naïve pluripotent state. Conclusions Altogether, our study highlights the topological regulation of ESRRB on MIR in the naïve potency state.
ISSN:1474-760X

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