A study published in Nature (2017) reveals two independent modes of chromatin organization. The research shows that deleting the cohesin-loading factor Nipbl in mouse liver leads to a dramatic reorganization of chromatin folding. TADs and associated peaks vanish globally, while compartmental segregation is preserved. The disappearance of TADs reveals a finer compartment structure that reflects the underlying epigenetic landscape. These findings demonstrate that the 3D organization of the genome results from two independent mechanisms: cohesin-independent segregation into fine-scale compartments defined by chromatin state, and cohesin-dependent formation of TADs, possibly by loop extrusion, which guides distant enhancers to their target genes. The study also shows that the loss of TADs and CTCF contact in Nipbl-depleted cells is not due to changes in CTCF occupancy. The changes in chromatin architecture are reflected in the curves of contact frequency P(s) as a function of genomic distance. The first scaling regime reflects the compaction of the genome associated with TADs. Simulations suggest that TADs would still be pronounced at 2-fold cohesin depletion, requiring ~8-fold depletion for loss of TADs. The study also reveals that the compartmentalization profile of the Nipbl-depleted Hi-C map reflects local transcriptional activity and chromatin state better than that of the WT Hi-C map. The compartment track of Nipbl-depleted cells shows a stronger correlation with tracks of activity-associated epigenetic marks. The absence of cohesin enhances the compartmentalization of active and inactive chromatin, with A and B regions forming fewer contacts between one another, and a finer compartment division emerging. The study also shows that transcriptional changes occurred upon TAD loss, with about a thousand genes significantly mis-expressed. The regulatory potential of the cells was mostly unperturbed, with new transcription often bi-directional and occurring at small pre-existing H3K4me3 peaks or active H3K27ac enhancers. The study concludes that cohesin is central to chromosome folding, with cohesin-independent mechanisms acting globally and across scales, and cohesin-dependent mechanisms compacting chromatin locally. The findings challenge the classic picture of genome architecture, showing that there are at least two mechanisms of independent origin whose overlapping action organizes mammalian interphase chromatin. The co-existence of two processes with different modes and scales of action helps explain the difficulties in delineating and unambiguously classifying the different features of Hi-C maps.A study published in Nature (2017) reveals two independent modes of chromatin organization. The research shows that deleting the cohesin-loading factor Nipbl in mouse liver leads to a dramatic reorganization of chromatin folding. TADs and associated peaks vanish globally, while compartmental segregation is preserved. The disappearance of TADs reveals a finer compartment structure that reflects the underlying epigenetic landscape. These findings demonstrate that the 3D organization of the genome results from two independent mechanisms: cohesin-independent segregation into fine-scale compartments defined by chromatin state, and cohesin-dependent formation of TADs, possibly by loop extrusion, which guides distant enhancers to their target genes. The study also shows that the loss of TADs and CTCF contact in Nipbl-depleted cells is not due to changes in CTCF occupancy. The changes in chromatin architecture are reflected in the curves of contact frequency P(s) as a function of genomic distance. The first scaling regime reflects the compaction of the genome associated with TADs. Simulations suggest that TADs would still be pronounced at 2-fold cohesin depletion, requiring ~8-fold depletion for loss of TADs. The study also reveals that the compartmentalization profile of the Nipbl-depleted Hi-C map reflects local transcriptional activity and chromatin state better than that of the WT Hi-C map. The compartment track of Nipbl-depleted cells shows a stronger correlation with tracks of activity-associated epigenetic marks. The absence of cohesin enhances the compartmentalization of active and inactive chromatin, with A and B regions forming fewer contacts between one another, and a finer compartment division emerging. The study also shows that transcriptional changes occurred upon TAD loss, with about a thousand genes significantly mis-expressed. The regulatory potential of the cells was mostly unperturbed, with new transcription often bi-directional and occurring at small pre-existing H3K4me3 peaks or active H3K27ac enhancers. The study concludes that cohesin is central to chromosome folding, with cohesin-independent mechanisms acting globally and across scales, and cohesin-dependent mechanisms compacting chromatin locally. The findings challenge the classic picture of genome architecture, showing that there are at least two mechanisms of independent origin whose overlapping action organizes mammalian interphase chromatin. The co-existence of two processes with different modes and scales of action helps explain the difficulties in delineating and unambiguously classifying the different features of Hi-C maps.