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HMGB1 as a rheostat of chromatin topology and RNA homeostasis on the path to senescence

Konstantinos Sofiadis, Milos Nikolic, Anne Zirkel, Yulia Kargapolova, Natasa Josipovic, Antonis Papadakis, Eduardo Gusmao, Athanasia Mizi, Theodore Georgomanolis, Mirjam Koker, Roland Ullrich, Janine Altmueller, Peter Nuernberg, Andreas Beyer, Argyris Papantonis
doi: https://doi.org/10.1101/540146
Konstantinos Sofiadis
University Medical Center Goettingen;
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Milos Nikolic
University of Cologne
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Anne Zirkel
University of Cologne
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Yulia Kargapolova
University of Cologne
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Natasa Josipovic
University Medical Center Goettingen;
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Antonis Papadakis
University of Cologne
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Eduardo Gusmao
University of Cologne
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Athanasia Mizi
University Medical Center Goettingen;
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Theodore Georgomanolis
University of Cologne
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Mirjam Koker
University of Cologne
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Roland Ullrich
University of Cologne
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Janine Altmueller
University of Cologne
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Peter Nuernberg
University of Cologne
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Andreas Beyer
University of Cologne
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Argyris Papantonis
University Medical Center Goettingen;
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  • For correspondence: argyris.papantonis@med.uni-goettingen.de
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Abstract

Spatial organization and gene expression of mammalian chromosomes are maintained and regulated in conjunction with cell cycle progression. This link is perturbed once cells enter senescence. The highly abundant HMGB1 protein, known to associate with bent and looped DNA, is actively depleted from senescent cell nuclei to act as an extracellular proinflammatory stimulus. Despite its physiological importance, we still lack understanding of the positioning and functional roles of HMGB1 on chromatin in vivo. To address this, we mapped HMGB1 binding genome-wide in different primary cells using a tailored protocol. We then integrated ChIP-seq and Hi-C data with a knot theory approach to uncover HMGB1 demarcation at the boundaries of particular topologically-associating domains (TADs). These TADs harbor genes involved in the key proinflammatory leg of the senescent transcriptional program. Moreover, we used sCLIP and siRNA-mediated knockdown to show that HMGB1 is a bona fide RNA-binding protein also affecting splicing choices. Together, our findings highlight a broader than hitherto assumed role for HMGB1 in chromatin homeostasis connected to cell cycle potency, and allow us to postulate a rheostat model for HMGB function with implications in cancer biology.

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Posted February 05, 2019.
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HMGB1 as a rheostat of chromatin topology and RNA homeostasis on the path to senescence
Konstantinos Sofiadis, Milos Nikolic, Anne Zirkel, Yulia Kargapolova, Natasa Josipovic, Antonis Papadakis, Eduardo Gusmao, Athanasia Mizi, Theodore Georgomanolis, Mirjam Koker, Roland Ullrich, Janine Altmueller, Peter Nuernberg, Andreas Beyer, Argyris Papantonis
bioRxiv 540146; doi: https://doi.org/10.1101/540146
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HMGB1 as a rheostat of chromatin topology and RNA homeostasis on the path to senescence
Konstantinos Sofiadis, Milos Nikolic, Anne Zirkel, Yulia Kargapolova, Natasa Josipovic, Antonis Papadakis, Eduardo Gusmao, Athanasia Mizi, Theodore Georgomanolis, Mirjam Koker, Roland Ullrich, Janine Altmueller, Peter Nuernberg, Andreas Beyer, Argyris Papantonis
bioRxiv 540146; doi: https://doi.org/10.1101/540146

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