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Genome models integrating chromatin contacts and nuclear lamin-genome interactions reveal implications of laminopathy-causing lamin mutations on genome architecture

ABSTRACT: Processes shaping the 3-dimensional (3D) human genome remain elusive. We present Chrom3D, a user-friendly 3D whole-genome modeling software that dynamically simulates the radial positioning of topological domains (TADs) in the nucleus. We integrate Hi-C and lamin-associated domain (LAD) information to generate high-resolution ensembles of models that recapitulate single-cell TAD distribution. Chrom3D reveals dynamic TADs and TADs constitutively placed at the nuclear periphery or nuclear interior. TAD stability in these compartments is consistent with differences in TAD gene density and expression level. A- and B-type lamins as radial constraints differentially skew LAD distribution towards the nuclear interior or periphery. Predictions of radial LAD placement in model ensembles are validated by quantitative imaging. Chrom3D models reveal unexpected features of LAD regulation in the nuclear interior in cells from laminopathy patients with a LMNA mutation. Integration of radial positioning constraints in 3D genome models enables the study spatial gene regulation in disease contexts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81671 | GEO | 2016/12/22

SECONDARY ACCESSION(S): PRJNA322286

REPOSITORIES: GEO

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