Klf5-adjacent super-enhancer functions as a 3D genome structure-dependent transcriptional driver to safeguard ESC identity

Guangsong Su, Bohan Chen, Yingjie Song, Qingqing Yin, Wenbin Wang, Xueyuan Zhao, Sibo Fan, Jie Lian, Dongqing Li, Jinfang Bi, Peng Li, Zhongfang Zhao, Lei Zhang, Jiandang Shi and Wange Lu ()
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Guangsong Su: Sun Yat-sen University
Bohan Chen: Sun Yat-sen University
Yingjie Song: Nankai University
Qingqing Yin: Nankai University
Wenbin Wang: Nankai University
Xueyuan Zhao: Nankai University
Sibo Fan: Nankai University
Jie Lian: Sun Yat-sen University
Dongqing Li: Sun Yat-sen University
Jinfang Bi: Sun Yat-sen University
Peng Li: Nankai University
Zhongfang Zhao: Nankai University
Lei Zhang: Nankai University
Jiandang Shi: Nankai University
Wange Lu: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Cell-specific super-enhancers (SEs) and master transcription factors (TFs) dynamically remodel embryonic stem cell (ESC) fate, yet their regulatory interplay remains unclear. By integrating multi-omics data (H3K27ac, Hi-C, scRNA-seq) across ESC states, we identified SEs interacting with master TFs, exemplified by the Klf5-adjacent SE (K5aSE). K5aSE deletion impaired proliferation, differentiation, and Klf5 expression, partially rescued by KLF5 reintroduction. Despite phenotypic similarities between Klf5-KO and K5aSE-KO ESCs, scRNA-seq of embryoid bodies revealed distinct differentiation trajectories, suggesting K5aSE targets beyond Klf5. High-throughput 3D genome screening demonstrated K5aSE activates four distal genes via chromatin looping. CRISPRa-mediated activation of these targets rescued K5aSE-KO phenotypes and uncovered their regulatory roles. Furthermore, CTCF depletion disrupted topologically associated domains (TADs) near K5aSE, suppressing Klf5 and target gene expression, indicating CTCF-mediated TADs sustain K5aSE activity. Our study unveils a 3D genome-dependent mechanism by which SEs govern ESC identity through coordinated TF interaction and multi-gene regulation.

Date: 2025
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DOI: 10.1038/s41467-025-60389-x

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