Abstract
Cell differentiation is a complex process characterized by specific gene expression patterns regulated through enhancer-promoter interactions within the three-dimensional architecture of the nucleus. The precise role of cohesin loading dynamics in restructuring chromatin during pancreatic lineage commitment remains unclear. Here we show that knockdown of cohesin loader NIPBL disrupts enhancer-promoter interactions and CTCF-mediated loops, leading to widespread transcriptional dysregulation. Furthermore, the loss of cohesin-mediated loops is accompanied by increased contacts between Polycomb Repressive Complex (PRC) domains, highlighting the interplay between cohesin dynamics and PRC-mediated compartmentalization. Although RAD21 and SA1 cohesin levels remain stable at CTCF loop anchors, NIPBL is essential for maintaining long-range chromatin interactions at later differentiation stages. These findings establish cohesin loading as a critical regulator of 3D genome reorganization during cell fate determination, providing a mechanistic framework for understanding cohesinopathy-related developmental disorders.
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Data availability
RNA-seq, ATAC-seq, ChIP-seq, and HiChIP data are accessible from NCBI’s Gene Expression Omnibus (GEO) under the accession number GSE288172. Hi-C data can be found under accession number GSE288728. Numerical source data underlying Fig. 4e are provided in Supplementary Data 2. Numerical source data underlying Fig. 5d–f are provided in Supplementary Data 3. Numerical source data underlying Figs. 6d and 7e are provided in Supplementary Data 4.
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Acknowledgements
We thank Dr. Victor Corces for critical reading of the manuscript and valuable suggestions. This work was supported by funds from National Key Research and Development Program of China (2022YFC2704802 to X.L.), National Natural Science Foundation of China (32470573 and 32170546 to X.L.), and National Key Research and Development Program of China (2021YFC2700303 to X.L.).
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X.L. and L.Y. designed the project. X.L. wrote the manuscript. L.Y., Y.L., J.Z., C.H., H.F., S.F., X.Z., and W.G. performed all experiments. X.L. and L.Y. performed data analyses.
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Yu, L., Liu, Y., Zhang, J. et al. Impaired cohesin loading disrupts pancreatic differentiation by Polycomb-driven chromatin rewiring and loop collapse. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09838-x
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DOI: https://doi.org/10.1038/s42003-026-09838-x
