Topological isolation of developmental regulators in mammalian genomes

Hua-Jun Wu, Alexandro Landshammer, Elena K. Stamenova, Adriano Bolondi, Helene Kretzmer, Alexander Meissner () and Franziska Michor ()
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Hua-Jun Wu: Peking University Health Science Center
Alexandro Landshammer: Department of Genome Regulation, Max Planck Institute for Molecular Genetics
Elena K. Stamenova: The Broad Institute of MIT and Harvard
Adriano Bolondi: Department of Genome Regulation, Max Planck Institute for Molecular Genetics
Helene Kretzmer: Department of Genome Regulation, Max Planck Institute for Molecular Genetics
Alexander Meissner: Department of Genome Regulation, Max Planck Institute for Molecular Genetics
Franziska Michor: The Broad Institute of MIT and Harvard

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24951-7

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