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Spatial reorganization of chromosome architecture in human stromal cells upon therapy-induced senescence

ABSTRACT: Cellular senescence is a basic biological process characterized by an essentially irreversible growth arrest. Senescent cells accumulate a variety of epigenetic alternations, but the three-dimensional (3D) organization of chromatin remains underexplored. We aim to characterize the 3D architecture of interphase chromosomes in proliferating, and therapy-induced senescent (TIS) cells of human stromal origin. Although the overall organization of chromatin into active (A) and repressive (B) compartments and topologically associated domains (TADs) is largely conserved between these conditions, a subset of TADs switches between compartments of proliferative versus TIS cells. On a global level, the Hi-C interaction matrices of senescent cells (TIS) are characterized by a relative gain of long-range, while a simultaneous loss of short-range interactions within chromosomes. Direct measurements of distances between genetic loci, chromosome volumes, and chromatin accessibility were performed. The structural model arising from this study provides a unique high-resolution view of the complex chromosomal architecture in human senescent cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193429 | GEO | 2026/01/14

REPOSITORIES: GEO

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Project description:The three-dimensional organization of chromosomes is tightly related to their biological function. Both imaging and chromosome conformation capture studies have revealed several layers of organization, including segregation into active and inactive compartments at the megabase scale, and partitioning into domains (TADs) and associated loops at the sub-megabase scale. Yet, it remains unclear how these layers of genome organization form, interact with one another, and contribute to or result from genome activities. TADs seem to have critical roles in regulating gene expression by promoting or preventing interactions between promoters and distant cis-acting regulatory elements, and different architectural proteins, including cohesin, have been proposed to play central roles in their formation. But so far, experimental depletions of these proteins have resulted in marginal changes in chromosome organization. Here, we show that deletion of the cohesin-loading factor, Nipbl, leads to loss of chromosome-associated cohesin and results in dramatic genome reorganization. TADs and associated loops vanish globally, even in the absence of transcriptional changes. In contrast, segregation into compartments is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the 3D organization of the genome results from the independent action of two distinct mechanisms: 1) cohesin-independent segregation of the genome into fine-scale compartment regions, defined by the underlying chromatin state; and 2) cohesin-dependent formation of TADs possibly by the recently proposed loop extrusion mechanism, enabling long-range and target-specific activity of promiscuous enhancers. The interplay between these mechanisms creates an architecture that is more complex than a simple structural hierarchy and can be central to guiding normal development.

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Spatial reorganization of chromosome architecture in human stromal cells upon therapy-induced senescence

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