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Review
. 2019 Jun;90:154-160.
doi: 10.1016/j.semcdb.2018.07.022. Epub 2018 Jul 27.

The Three-Dimensional Organization of the Genome in Cellular Senescence and Age-Associated Diseases

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Free PMC article
Review

The Three-Dimensional Organization of the Genome in Cellular Senescence and Age-Associated Diseases

Shane A Evans et al. Semin Cell Dev Biol. .
Free PMC article

Abstract

Recent advances in genomics and imaging technologies have increased our ability to interrogate the 3D conformation of chromosomes and to better understand principles of organization and dynamics, as well as how their alteration can lead to disease. In this review we describe how these technologies have shed new light into the role of the 3D organization of the genome in defining cellular states in aging and age-associated diseases. We compare the genomic organization in cellular senescence and cancer, discuss the role of the lamina in maintaining the structural and functional integrity of the genome, and we highlight the recent findings on how this organization breaks down in disease states.

Keywords: Aging; Cancer; Cytoplasmic DNA; Hi-C; Inflammation; Senescence.

Figures

Figure 1
Figure 1
Example of a Hi-C contact map for a chromosome subregion (left). High intensity indicates the corresponding pair of genomic loci display many contacts between them. Typical features are indicated with colored boxes: a Topologically associated domain (TAD) (black), a loop anchor (blue), contact depleted region between TADs (green). Contact matrices can be used to infer the 3D structure of chromosomes (right).
Figure 2
Figure 2
Schematic of some of the known 3D perturbations which can elicit different disease states. Impaired genome nuclear lamina interaction is associated with cellular senescence as well as causal to laminopathies such as Hutchinson-Gilford progeria syndrome (left). TAD disruption can lead to aberrant gene expression, contributing to hyperproliferation and cancer (center). Progressive telomere shortening can regulate gene expression over long distances, a process called Telomere position effect (TPE), and can lead to pathologies such as Facioscapulohumeral muscular dystrophy (FSHD) through the activation of the DUX4 locus.
Figure 3
Figure 3
Nuclear dysmorphism and cytosolic DNA in cancer and senescent cells are precursors to inflammation. Nuclei from cancer and senescent cells share common aberrant nuclear structural properties such as nuclear envelope distensions (blebs) and altered lamin expression. In the cancer nucleus, nuclear blebbing and micronuclei are formed due to genotoxic stresses, lamin A/C (red) or lamin B (blue) dysregulation, and excessive force of perinuclear structural proteins (neon blue). In senescent cells the 3D genome changes represented by dissociation of chromatin (grey) from regions of the nuclear lamina. Lamin B1 (blue) is targeted for degradation with its associated DNA (grey) and is extruded into the cytosol via LC3II (yellow). Detection of aberrant DNA species in the cytosol of cancer and senescent cells by cGAS-STING, propagates a pro-inflammatory type I interferon response.

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