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

Aled J. Parry, Matthew Hoare, Dóra Bihary, Robert Hänsel-Hertsch, Stephen Smith, Kosuke Tomimatsu, Elizabeth Mannion, Amy Smith, Paula D’Santos, I. Alasdair Russell, Shankar Balasubramanian, Hiroshi Kimura, Shamith A. Samarajiwa () and Masashi Narita ()
Additional contact information
Aled J. Parry: University of Cambridge
Matthew Hoare: University of Cambridge
Dóra Bihary: University of Cambridge
Robert Hänsel-Hertsch: University of Cambridge
Stephen Smith: University of Cambridge
Kosuke Tomimatsu: University of Cambridge
Elizabeth Mannion: University of Cambridge
Amy Smith: University of Cambridge
Paula D’Santos: University of Cambridge
I. Alasdair Russell: University of Cambridge
Shankar Balasubramanian: University of Cambridge
Hiroshi Kimura: Tokyo Institute of Technology
Shamith A. Samarajiwa: University of Cambridge
Masashi Narita: University of Cambridge

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04283-9

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