Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 12, Pages E1691-E1700Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1521826113
Keywords
cell differentiation; gene regulation; nuclear organization; transcriptional noise; 3D image analysis
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Funding
- National Cancer Institute Grant [CCSG P30 CA060553]
- National Institutes of Health New Innovator Award [DP2 OD008717-01]
- National Institute of General Medical Sciences Cellular and Molecular Basis of Disease Training Grant [T32 GM08061]
- National Cancer Institute Oncogenesis and Developmental Biology Training Grant [T32 CA080621]
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The linear distribution of genes across chromosomes and the spatial localization of genes within the nucleus are related to their transcriptional regulation. The mechanistic consequences of linear gene order, and how it may relate to the functional output of genome organization, remain to be fully resolved, however. Here we tested the relationship between linear and 3D organization of gene regulation during myogenesis. Our analysis has identified a subset of topologically associated domains (TADs) that are significantly enriched for muscle-specific genes. These lineage-enriched TADs demonstrate an expression-dependent pattern of nuclear organization that influences the positioning of adjacent nonenriched TADs. Therefore, lineage-enriched TADs inform cell-specific genome organization during myogenesis. The reduction of allelic spatial distance of one of these domains, which contains Myogenin, correlates with reduced transcriptional variability, identifying a potential role for lineage-specific nuclear topology. Using a fusion-based strategy to decouple mitosis and myotube formation, we demonstrate that the cell-specific topology of syncytial nuclei is dependent on cell division. We propose that the effects of linear and spatial organization of gene loci on gene regulation are linked through TAD architecture, and that mitosis is critical for establishing nuclear topologies during cellular differentiation.
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