Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-24951-7
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Funding
- Dana-Farber Cancer Institute Physical Sciences-Oncology Center, NIH [U54CA193461]
- Max Planck Society
- High-performance Computing Platform of Peking University
- NIH [1P50HG006193, P01GM099117, 1DP3K111898]
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The disruption of a SOX17 boundary in human pluripotent stem cells interferes with proper differentiation, and germline variations affecting such boundaries are selectively retained, leading to underrepresentation in the human population.
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. The phenotypic consequence of 3D genome boundary disruption on developmental processes remains insufficiently understood. Here, the authors show that perturbation of a SOX17 boundary in human pluripotent stem cells interferes with proper differentiation and that germline variations affecting such boundaries are subject to selection, resulting in underrepresentation in the human population.
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