1. Topological isolation of developmental regulators in mammalian genomes.
- Author
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Wu HJ, Landshammer A, Stamenova EK, Bolondi A, Kretzmer H, Meissner A, and Michor F
- Subjects
- Binding Sites genetics, Blotting, Western, CCCTC-Binding Factor genetics, CCCTC-Binding Factor metabolism, Cell Line, Enhancer Elements, Genetic genetics, Human Embryonic Stem Cells cytology, Humans, Induced Pluripotent Stem Cells cytology, Promoter Regions, Genetic genetics, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA methods, Cell Differentiation genetics, Gene Expression Profiling methods, Genome, Human genetics, Human Embryonic Stem Cells metabolism, Induced Pluripotent Stem Cells metabolism, Regulatory Elements, Transcriptional genetics
- Abstract
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., (© 2021. The Author(s).)
- Published
- 2021
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