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Topological isolation as a mechanism for precise control of developmental regulators in mammalian genomes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127196 | GEO | 2021/06/06

REPOSITORIES: GEO

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Topological isolation as a mechanism for precise control of developmental regulators in mammalian genomes [HiC]

Project description:Developmental regulators are spatiotemporal regulated in the process of human development. Recent investigation of insulated chromosome structures suggests their crucial role in control of proper gene expression. However, it’s unclear whether developmental regulators can be precisely controlled by such insulated structures and whether developmental failure can be caused by disrupting the structure boundaries. Here we identified topologically insulated regions (TIRs) from deeply sequenced human embryonic stem cell (hESC) Hi-C data and analyzed the gene distribution across TIRs. We found a notable enrichment of developmental regulators isolated from other genes by TIRs and show that the boundary CTCF sites are highly conserved across species. Perturbation of such boundaries in hESCs leads to the differentiation failure. Germline mutations affecting such boundaries are subject to purifying selection, and are underrepresented in the human population. Further analyses demonstrated the enhancer activity is restricted by such boundaries that further points towards regulatory importance. Our findings provide new insights into mammalian genome organization and including a possible role of gene insulation through chromosomal folding structures for precise control of developmental regulators.

2021-06-06 | GSE130085 | GEO

Topological isolation as a mechanism for precise control of developmental regulators in mammalian genomes [RNA-seq]

Project description:Recent investigation of insulated chromosome structures suggests their crucial role in controlling proper gene expression. However, it remains unclear whether developmental regulators can be precisely controlled by such insulated structures and whether developmental failure is caused by disrupting the structure boundaries. Here we identified topologically insulated regions (TIRs) from deeply sequenced human embryonic stem cell (hESC) Hi-C data and analyzed the gene distribution across TIRs. We find a notable enrichment of developmental regulators isolated from other genes by TIRs and show that the boundary CTCF sites are highly conserved across species. Perturbation of such boundaries in hESCs leads to failure to properly differentiate. Enhancer activity is restricted by such boundaries, further pointing towards their regulatory importance. Finally, germline mutations affecting such boundaries are subject to purifying selection and are underrepresented in the human population. Our findings provide new insights into mammalian genome organization and suggest a possible role of gene insulation through chromosomal folding structures for precise control of developmental regulators.

2021-06-06 | GSE127194 | GEO

Topological isolation as a mechanism for precise control of developmental regulators in mammalian genomes [4C-seq]

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Topological isolation as a mechanism for precise control of developmental regulators in mammalian genomes (Hi-C II)

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Topological isolation as a mechanism for precise control of developmental regulators in mammalian genomes [RNA-seq II]

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Topological isolation of developmental regulators in mammalian genomes.

Project description:Precise control of mammalian gene expression is facilitated through epigenetic mechanisms and nuclear organization. In particular, insulated chromosome structures are important for regulatory control, but the phenotypic consequences of their boundary disruption on developmental processes are complex and remain insufficiently understood. Here, we generated deeply sequenced Hi-C data for human pluripotent stem cells (hPSCs) that allowed us to identify CTCF loop domains that have highly conserved boundary CTCF sites and show a notable enrichment of individual developmental regulators. Importantly, perturbation of such a boundary in hPSCs interfered with proper differentiation through deregulated distal enhancer-promoter activity. Finally, we found that germline variations affecting such boundaries are subject to purifying selection and are underrepresented in the human population. Taken together, our findings highlight the importance of developmental gene isolation through chromosomal folding structures as a mechanism to ensure their proper expression.

| S-EPMC8361032 | biostudies-literature