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, Masashi Narita

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

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.

Original languageEnglish
Article number1840
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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