Project description:Physical interactions between distal regulatory elements in the genome play a key role in regulating gene expression, yet the extent to which these interactions vary between cell types and contribute to cell type-specific gene expression patterns remains unclear. To address this question we have mapped cohesin-bound chromatin loops in 24 diverse human cell types at high resolution using the chromatin interaction analysis by paired-end tag (ChIA-PET) sequencing approach. We combined a total of ~9.6 billion reads across all samples to generate a compendium of 124,830 loops, the most extensive resource currently available. We find that 39% of all chromatin loops vary across cell types, and such changes are effective at grouping cell types based on their tissue of origin, indicating commonalities in three-dimensional (3D) genome architecture amongst related cell types. In contrast, different cell types derived from the same individual show markedly different patterns of interactions indicating that the observed differences are mainly caused by epigenetic changes. Variation in chromatin loops correlates with changes in gene expression, especially for long-range contacts linking cell type-specific enhancers to promoters; moreover, genes contained within the same loop show coordinated co-expression changes in expression across cell types. We further find that loops specific to either blood or embryonic cell lines harbor distinct sets of genes relevant to cell type-specific function, and are enriched for lineage determining transcription factors, indicating a possible mechanism for the assembly of variable loops. Finally, we demonstrate that genetic variants identified in GWAS are enriched in variable loops in disease relevant cell types. Our results provide important insights in how changes in 3D chromatin organization potentially regulate cell type-specific functions.
Project description:Understanding the impact of cohesin mutations on HSPC chromatin structure We examined chromatin structure using ATAC-seq in CD34+ enriched-human HSPC that were transduced with either cohesin WT, mutant or empty vector controls
Project description:Physical interactions between distal regulatory elements in the genome play a key role in regulating gene expression, yet the extent to which these interactions vary between cell types and contribute to cell type-specific gene expression patterns remains unclear. To address this question we have mapped cohesin-bound chromatin loops in 24 diverse human cell types at high resolution using the chromatin interaction analysis by paired-end tag (ChIA-PET) sequencing approach. We combined a total of ~9.6 billion reads across all samples to generate a compendium of 124,830 loops, the most extensive resource currently available. We find that 39% of all chromatin loops vary across cell types, and such changes are effective at grouping cell types based on their tissue of origin, indicating commonalities in three-dimensional (3D) genome architecture amongst related cell types. In contrast, different cell types derived from the same individual show markedly different patterns of interactions indicating that the observed differences are mainly caused by epigenetic changes. Variation in chromatin loops correlates with changes in gene expression, especially for long-range contacts linking cell type-specific enhancers to promoters; moreover, genes contained within the same loop show coordinated co-expression changes in expression across cell types. We further find that loops specific to either blood or embryonic cell lines harbor distinct sets of genes relevant to cell type-specific function, and are enriched for lineage determining transcription factors, indicating a possible mechanism for the assembly of variable loops. Finally, we demonstrate that genetic variants identified in GWAS are enriched in variable loops in disease relevant cell types. Our results provide important insights in how changes in 3D chromatin organization potentially regulate cell type-specific functions.
Project description:Physical interactions between distal regulatory elements in the genome play a key role in regulating gene expression, yet the extent to which these interactions vary between cell types and contribute to cell type-specific gene expression patterns remains unclear. To address this question we have mapped cohesin-bound chromatin loops in 24 diverse human cell types at high resolution using the chromatin interaction analysis by paired-end tag (ChIA-PET) sequencing approach. We combined a total of ~9.6 billion reads across all samples to generate a compendium of 124,830 loops, the most extensive resource currently available. We find that 39% of all chromatin loops vary across cell types, and such changes are effective at grouping cell types based on their tissue of origin, indicating commonalities in three-dimensional (3D) genome architecture amongst related cell types. In contrast, different cell types derived from the same individual show markedly different patterns of interactions indicating that the observed differences are mainly caused by epigenetic changes. Variation in chromatin loops correlates with changes in gene expression, especially for long-range contacts linking cell type-specific enhancers to promoters; moreover, genes contained within the same loop show coordinated co-expression changes in expression across cell types. We further find that loops specific to either blood or embryonic cell lines harbor distinct sets of genes relevant to cell type-specific function, and are enriched for lineage determining transcription factors, indicating a possible mechanism for the assembly of variable loops. Finally, we demonstrate that genetic variants identified in GWAS are enriched in variable loops in disease relevant cell types. Our results provide important insights in how changes in 3D chromatin organization potentially regulate cell type-specific functions.
Project description:Cohesin catalyses the folding of the genome into loops that are anchored by CTCF. The molecular mechanism of how cohesin and CTCF structure the 3D genome has remained unclear. Here we show that a segment within the CTCF N terminus interacts with the SA2-SCC1 subunits of cohesin. A 2.6 Ă… crystal structure of SA2-SCC1 in complex with CTCF reveals the molecular basis of the interaction. We demonstrate that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF-binding sites. A similar motif is present in a number of established and novel cohesin ligands, including the cohesin release factor WAPL. Our data suggest that CTCF enables chromatin loop formation by protecting cohesin against loop release. These results provide fundamental insights into the molecular mechanism that enables dynamic regulation of chromatin folding by cohesin and CTCF.
Project description:Cohesin catalyses the folding of the genome into loops that are anchored by CTCF. The molecular mechanism of how cohesin and CTCF structure the 3D genome has remained unclear. Here we show that a segment within the CTCF N terminus interacts with the SA2-SCC1 subunits of cohesin. A 2.6 Ă… crystal structure of SA2-SCC1 in complex with CTCF reveals the molecular basis of the interaction. We demonstrate that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF-binding sites. A similar motif is present in a number of established and novel cohesin ligands, including the cohesin release factor WAPL. Our data suggest that CTCF enables chromatin loop formation by protecting cohesin against loop release. These results provide fundamental insights into the molecular mechanism that enables dynamic regulation of chromatin folding by cohesin and CTCF.
Project description:Cohesin catalyses the folding of the genome into loops that are anchored by CTCF. The molecular mechanism of how cohesin and CTCF structure the 3D genome has remained unclear. Here we show that a segment within the CTCF N terminus interacts with the SA2-SCC1 subunits of cohesin. A 2.6 Ă… crystal structure of SA2-SCC1 in complex with CTCF reveals the molecular basis of the interaction. We demonstrate that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF-binding sites. A similar motif is present in a number of established and novel cohesin ligands, including the cohesin release factor WAPL. Our data suggest that CTCF enables chromatin loop formation by protecting cohesin against loop release. These results provide fundamental insights into the molecular mechanism that enables dynamic regulation of chromatin folding by cohesin and CTCF.