The study investigates the role of Mediator and Cohesin in connecting gene expression and chromatin architecture. Transcription factors control gene expression through interactions with coactivators like Mediator and the transcription apparatus. The process of gene activation involves DNA looping between enhancers and core promoters, but the mechanisms are not well understood. The authors found that Mediator and Cohesin physically and functionally connect the enhancers and core promoters of active genes in embryonic stem (ES) cells. Mediator, a transcriptional coactivator, forms complexes with Cohesin, which can form rings connecting two DNA segments. The Cohesin loading factor Nipbl is associated with these complexes, facilitating their loading at promoters. DNA looping is observed between enhancers and promoters occupied by Mediator and Cohesin. Mediator and Cohesin occupy different promoters in different cells, generating cell-type specific DNA loops linked to gene expression programs. The study also shows that Mediator, Cohesin, and Nipbl interact and co-occupy active genes, suggesting their collaborative role in gene regulation. Furthermore, the co-occupancy of these complexes predicts DNA looping events between enhancers and promoters, and their occupancy patterns are cell-type specific. These findings highlight the importance of Mediator, Cohesin, and Nipbl in linking gene expression and cell-type specific chromatin structure.The study investigates the role of Mediator and Cohesin in connecting gene expression and chromatin architecture. Transcription factors control gene expression through interactions with coactivators like Mediator and the transcription apparatus. The process of gene activation involves DNA looping between enhancers and core promoters, but the mechanisms are not well understood. The authors found that Mediator and Cohesin physically and functionally connect the enhancers and core promoters of active genes in embryonic stem (ES) cells. Mediator, a transcriptional coactivator, forms complexes with Cohesin, which can form rings connecting two DNA segments. The Cohesin loading factor Nipbl is associated with these complexes, facilitating their loading at promoters. DNA looping is observed between enhancers and promoters occupied by Mediator and Cohesin. Mediator and Cohesin occupy different promoters in different cells, generating cell-type specific DNA loops linked to gene expression programs. The study also shows that Mediator, Cohesin, and Nipbl interact and co-occupy active genes, suggesting their collaborative role in gene regulation. Furthermore, the co-occupancy of these complexes predicts DNA looping events between enhancers and promoters, and their occupancy patterns are cell-type specific. These findings highlight the importance of Mediator, Cohesin, and Nipbl in linking gene expression and cell-type specific chromatin structure.