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- Title
HMGB1 coordinates SASP‐related chromatin folding and RNA homeostasis on the path to senescence.
- Authors
Sofiadis, Konstantinos; Josipovic, Natasa; Nikolic, Milos; Kargapolova, Yulia; Übelmesser, Nadine; Varamogianni‐Mamatsi, Vassiliki; Zirkel, Anne; Papadionysiou, Ioanna; Loughran, Gary; Keane, James; Michel, Audrey; Gusmao, Eduardo G; Becker, Christian; Altmüller, Janine; Georgomanolis, Theodore; Mizi, Athanasia; Papantonis, Argyris
- Abstract
Spatial organization and gene expression of mammalian chromosomes are maintained and regulated in conjunction with cell cycle progression. This is perturbed once cells enter senescence and the highly abundant HMGB1 protein is depleted from nuclei to act as an extracellular proinflammatory stimulus. Despite its physiological importance, we know little about the positioning of HMGB1 on chromatin and its nuclear roles. To address this, we mapped HMGB1 binding genome‐wide in two primary cell lines. We integrated ChIP‐seq and Hi‐C with graph theory to uncover clustering of HMGB1‐marked topological domains that harbor genes involved in paracrine senescence. Using simplified Cross‐Linking and Immuno‐Precipitation and functional tests, we show that HMGB1 is also a bona fide RNA‐binding protein (RBP) binding hundreds of mRNAs. It presents an interactome rich in RBPs implicated in senescence regulation. The mRNAs of many of these RBPs are directly bound by HMGB1 and regulate availability of SASP‐relevant transcripts. Our findings reveal a broader than hitherto assumed role for HMGB1 in coordinating chromatin folding and RNA homeostasis as part of a regulatory loop controlling cell‐autonomous and paracrine senescence. Synopsis: Mammalian cell senescence entry is marked by the nuclear loss of HMGB1. Genome‐wide analyses show that HMGB1 binds both chromatin and mRNAs in proliferating cells, and its loss underlies topological and splicing changes inducing the senescent transcriptional program. Senescence entry by mammalian cells is marked by the nuclear depletion of HMGB1.HMGB1 shows dual specificity binding to a subset of topological boundaries on chromatin and to hundreds of mRNAs.TAD clusters enriched for HMGB1 spatially co‐associate in proliferating cell nuclei.HMGB1 loss leads to transcriptional changes necessary for senescence establishment.
- Subjects
CELLULAR aging; RNA-binding proteins; RNA; CELL cycle; GRAPH theory; CHROMATIN
- Publication
Molecular Systems Biology, 2021, Vol 17, Issue 6, p1
- ISSN
1744-4292
- Publication type
Article
- DOI
10.15252/msb.20209760