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Mol Cell. 2018 May 17;70(4):730-744.e6. doi: 10.1016/j.molcel.2018.03.030. Epub 2018 Apr 26.

HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types.

Author information

1
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
2
German Cancer Research Center and Bioquant, 69120 Heidelberg, Germany.
3
School of Physics and Astronomy, University of Edinburgh, EH9 3FD Edinburgh, UK.
4
Institute of Molecular Biology, 55128 Mainz, Germany.
5
Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
6
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
7
Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Medical School, 52074 Aachen, Germany.
8
Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne, 50931 Cologne, Germany.
9
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Interdisciplinary Centre for Clinical Research, RWTH Aachen University Medical School, 52062 Aachen, Germany.
10
Interdisciplinary Centre for Clinical Research, RWTH Aachen University Medical School, 52062 Aachen, Germany.
11
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Clinic I of Internal Medicine and Center for Integrated Oncology, University Hospital Cologne, 50931 Cologne, Germany.
12
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
13
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany. Electronic address: argyris.papantonis@uni-koeln.de.

Abstract

Processes like cellular senescence are characterized by complex events giving rise to heterogeneous cell populations. However, the early molecular events driving this cascade remain elusive. We hypothesized that senescence entry is triggered by an early disruption of the cells' three-dimensional (3D) genome organization. To test this, we combined Hi-C, single-cell and population transcriptomics, imaging, and in silico modeling of three distinct cells types entering senescence. Genes involved in DNA conformation maintenance are suppressed upon senescence entry across all cell types. We show that nuclear depletion of the abundant HMGB2 protein occurs early on the path to senescence and coincides with the dramatic spatial clustering of CTCF. Knocking down HMGB2 suffices for senescence-induced CTCF clustering and for loop reshuffling, while ectopically expressing HMGB2 rescues these effects. Our data suggest that HMGB2-mediated genomic reorganization constitutes a primer for the ensuing senescent program.

KEYWORDS:

CTCF loops; Hi-C; TAD boundary; chromatin organization; compartment; high-mobility group protein; interaction; senescence

PMID:
29706538
DOI:
10.1016/j.molcel.2018.03.030
[Indexed for MEDLINE]

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