title: Topologically associated domains enriched for lineage-specific genes reveal expression-dependent nuclear topologies during myogenesis.
abstract: 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.
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Neems
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Arturo G
authors.initials: AG
authors.lastname: Garza-Gongora
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Erica D
authors.initials: ED
authors.lastname: Smith
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 s-kosak@northwestern.edu.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Kosak
mesh_terms: D000483:Alleles; D019070:Cell Lineage / Q000235:genetics*; D002874:Chromosome Mapping; D005347:Fibroblasts; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D021621:Imaging, Three-Dimensional; D017404:In Situ Hybridization, Fluorescence; D024510:Muscle Development / Q000235:genetics*; D017570:MyoD Protein / Q000235:genetics; D018008:Myogenin / Q000235:genetics; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic; D014161:Transduction, Genetic
chemical_list: C503799:MYOG protein, human; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D018008:Myogenin; D049452:Green Fluorescent Proteins
keywords: 3D image analysis; cell differentiation; gene regulation; nuclear organization; transcriptional noise