PT  - JOURNAL ARTICLE
AU  - Aled J. Parry
AU  - Matthew Hoare
AU  - Dóra Bihary
AU  - Robert Hänsel-Hertsch
AU  - Stephen Smith
AU  - Kosuke Tomimatsu
AU  - Shankar Balasubramanian
AU  - Hiroshi Kimura
AU  - Shamith A. Samarajiwa
AU  - Masashi Narita
TI  - NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence
AID  - 10.1101/212829
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 212829
4099  - http://biorxiv.org/content/early/2017/11/02/212829.short
4100  - http://biorxiv.org/content/early/2017/11/02/212829.full
AB  - Senescent cells interact with the surrounding microenvironment achieving diverse functional outcomes. In addition to autocrine and paracrine signalling mediated by factors of the senescence-associated secretory phenotype, we have recently identified that NOTCH1 can drive ‘lateral induction’ of a unique form of senescence in adjacent cells through specific induction of the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure both autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells in culture exhibit a massive increase in nucleosome-free regions (NRFs). NOTCH signalling suppresses both SAHF and NFR formation in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, also 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 a range of human cancers. Thus, HMGA1 is involved not only in SAHFs, but also RIS-specific NFR formation. In conclusion, this study identifies that the JAG1-NOTCH-HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.