HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence

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 RNAbinding 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.

HMGB1 orchestrates STING-mediated senescence via TRIM30α modulation in cancer cells

“…For example, in some studies, HMGB1 has been shown to promote cancer development and chemotherapy resistance; however, in other studies, HMGB1 exhibits tumor-suppressive activities 13 . HMGB1 is also associated with senescence [14][15][16][17] , although its role in cGAS/STING-dependent senescence in cancer cells has not been determined.…”