Cross-species regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE229101 | GEO | 2023/04/10
REPOSITORIES: GEO
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Project description:Knowledge of the locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to better understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using multiple epigenetic features in cell types from one species at a time, but such an approach can make it difficult to compare results across species. In contrast, we conducted a cross-species study defining epigenetic states and identifying cCREs in blood cell types to generate maps of the regulatory landscapes and cCREs that are comparable across species. This study used integrative modeling of eight epigenetic features jointly in both human and mouse in our Validated Systematic Integration (VISION) Project. The accuracy of the cCRE predictions was supported by orthogonal function-related data. The contribution of each epigenetic state in cCREs to gene regulation was estimated from a multivariate regression against gene expression across cell types, and these values were used to estimate an epigenetic state Regulatory Potential (esRP) score for each cCRE in each cell type. These esRP scores have broad utility for visualizing and categorizing the dynamic changes in cCREs during hematopoietic differentiation. After jointly clustering cCREs based on their esRP scores across human and mouse cell types, we found distinctive transcription factor binding motifs associated with each group of cCREs with similar patterns of regulatory activity; these associations are similar between human and mouse. Genetic variants associated with blood cell phenotypes (from the GWAS Catalog and the UK Biobank study) were highly and specifically enriched in the catalog of human VISION cCREs, indicating the utility of our cCRE predictions for understanding the impact of noncoding genetic variants on both physiologic and pathologic blood cell-related traits. The cross-species joint modeling enabled a comparison of cCREs that revealed both conserved and lineage-specific patterns of epigenetic evolution, even in the absence of genomic sequence alignment. The VISION project resources are accessible through a suite of tools and browsers at http://usevision.org.
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Project description:Knowledge of the locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to better understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using multiple epigenetic features in cell types from one species at a time, but such an approach can make it difficult to compare results across species. In contrast, we conducted a cross-species study defining epigenetic states and identifying cCREs in blood cell types to generate maps of the regulatory landscapes and cCREs that are comparable across species. This study used integrative modeling of eight epigenetic features jointly in both human and mouse in our Validated Systematic Integration (VISION) Project. The accuracy of the cCRE predictions was supported by orthogonal function-related data. The contribution of each epigenetic state in cCREs to gene regulation was estimated from a multivariate regression against gene expression across cell types, and these values were used to estimate an epigenetic state Regulatory Potential (esRP) score for each cCRE in each cell type. These esRP scores have broad utility for visualizing and categorizing the dynamic changes in cCREs during hematopoietic differentiation. After jointly clustering cCREs based on their esRP scores across human and mouse cell types, we found distinctive transcription factor binding motifs associated with each group of cCREs with similar patterns of regulatory activity; these associations are similar between human and mouse. Genetic variants associated with blood cell phenotypes (from the GWAS Catalog and the UK Biobank study) were highly and specifically enriched in the catalog of human VISION cCREs, indicating the utility of our cCRE predictions for understanding the impact of noncoding genetic variants on both physiologic and pathologic blood cell-related traits. The cross-species joint modeling enabled a comparison of cCREs that revealed both conserved and lineage-specific patterns of epigenetic evolution, even in the absence of genomic sequence alignment. The VISION project resources are accessible through a suite of tools and browsers at http://usevision.org.
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Project description:Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.
| S-EPMC10103973 | biostudies-literature
Project description:Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state regulatory potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbor distinctive transcription factor binding motifs that are similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we show that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.
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Project description:Cross-species regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes
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Project description:Cross-species regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes [mouse TFbs]
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Project description:Cross-species regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes [human ChIP]
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Project description:Cross-species regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes [mouse histones]
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