Interplay between cohesin and RNA polymerase II in regulating chromatin interactions and gene transcription.

Authors

• Minji Kim, The Jackson LaboratoryFollow
• Ping Wang, The Jackson LaboratoryFollow
• Patricia A Clow, The Jackson LaboratoryFollow
• Eli Chien
• Xiaotao Wang
• Jianhao Peng
• Haoxi Chai, The Jackson LaboratoryFollow
• Xiyuan Liu, The Jackson Laboratory
• Byoungkoo Lee, The Jackson LaboratoryFollow
• Chew Yee Ngan, The Jackson LaboratoryFollow
• Olgica Milenkovic
• Jeffrey ChuangFollow
• Chia-Lin Wei, The Jackson LaboratoryFollow
• Rafael Casellas
• Albert Cheng, The Jackson LaboratoryFollow
• Yijun Ruan, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

2-1-2026

Original Citation

Kim M, Wang P, Clow P, Chien E, Wang X, Peng J, Chai H, Liu X, Lee B, Ngan C, Milenkovic O, Chuang J, Wei C, Casellas R, Cheng A, Ruan Y. Interplay between cohesin and RNA polymerase II in regulating chromatin interactions and gene transcription. Nat Struct Mol Biol. 2026;33(2):259–74

Keywords

JGM, RNA Polymerase II, Cohesins, Humans, Chromosomal Proteins, Non-Histone, Cell Cycle Proteins, Chromatin, Transcription, Genetic, Nuclear Proteins, Phosphoproteins, Gene Expression Regulation, DNA Replication, Promoter Regions, Genetic, Adenosine Triphosphatases, DNA-Binding Proteins

JAX Source

Nat Struct Mol Biol. 2026;33(2):259–74

ISSN

1545-9985

PMID

41530636

DOI

https://doi.org/10.1038/s41594-025-01708-0

Grant

This study was supported by National Natural Science Foundation of China (32250710678 to Y.R.), the Jackson Laboratory Director’s Innovation Fund (DIF19000-18-02 to Y.R.), 4DN (U54 DK107967 to Y.R.), ENCODE (UM1 HG009409 to Y.R.) consortia, Human Frontier Science Program (RGP0039/2017 to Y.R.), the National Human Genome Research Institute (R01-HG009900 to A.W.C., R01-HG011253 to C.-L.W., R01-GM127531 to C.-L.W., K99-HG011542 to M.K.), and National Science Foundation (CCF-1955712 to O.M., CIF 1956384 to O.M.)

Abstract

Cohesin is required for chromatin loop formation. However, its precise role in regulating gene transcription remains largely debated. Here we investigated the relationship between cohesin and RNA polymerase II (RNAPII) using single-molecule mapping and live-cell imaging methods in human cells. Cohesin-mediated transcriptional loops were highly correlated with those of RNA polymerase II and followed the direction of gene transcription. Depleting RAD21, a subunit of cohesin, resulted in the loss of long-range (>100 kb) loops between distal (super-)enhancers and promoters of cell-type-specific downregulated genes. By contrast, short-range (< 50 kb) loops were insensitive to RAD21 depletion and connected genes that are mostly constitutively expressed. This result explains why only a small fraction of genes are affected by the loss of long-range chromatin interactions in cohesin-depleted cells. Remarkably, RAD21 depletion appeared to upregulate genes that were involved in initiating DNA replication and disrupted DNA replication timing. Our results elucidate the multifaceted roles of cohesin in establishing transcriptional loops, preserving long-range chromatin interactions for cell-specific genes and maintaining timely DNA replication.