NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence.


Type
Article
Change log
Authors
Hoare, Matthew 
Bihary, Dóra 
Hänsel-Hertsch, Robert 
Abstract

Senescent cells interact with the surrounding microenvironment achieving diverse functional outcomes. We have recently identified that NOTCH1 can drive 'lateral induction' of a unique senescence phenotype in adjacent cells by specifically upregulating the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells exhibit a massive increase in chromatin accessibility. NOTCH signalling suppresses SAHF and increased chromatin accessibility in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, drive similar chromatin architectural changes in adjacent cells through cell-cell contact. Mechanistically, we show that NOTCH signalling represses the chromatin architectural protein HMGA1, an association found in multiple human cancers. Thus, HMGA1 is involved not only in SAHFs but also in RIS-driven chromatin accessibility. In conclusion, this study identifies that the JAG1-NOTCH-HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.

Description
Keywords
Cellular Senescence, Chromatin, HMGA1a Protein, Heterochromatin, Humans, Jagged-1 Protein, Receptor, Notch1, Signal Transduction
Journal Title
Nat Commun
Conference Name
Journal ISSN
2041-1723
2041-1723
Volume Title
9
Publisher
Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MR/M013049/1)
Cancer Research UK (C14303/A17197)
Cancer Research UK (C20/A20976)
Medical Research Council (MR/R010013/1)
Cancer Research UK (CB4330)
Cancer Research UK (CB4210)
Cancer Research UK (19924)
Medical Research Council (MR/R001146/1)
MRC (unknown)
MRC
Cancer Research UK (CB4160)
MRC (MC_UU_12022/10)
Cancer Research UK (A19924)