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

Author

Listed:
  • Aled J. Parry

    (University of Cambridge)

  • Matthew Hoare

    (University of Cambridge
    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
    University of Cambridge)

  • Hiroshi Kimura

    (Tokyo Institute of Technology)

  • Shamith A. Samarajiwa

    (University of Cambridge)

  • Masashi Narita

    (University of Cambridge)

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.

Suggested Citation

  • 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 , 2018. "NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04283-9
    DOI: 10.1038/s41467-018-04283-9
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    Cited by:

    1. Ioana Olan & Masami Ando-Kuri & Aled J. Parry & Tetsuya Handa & Stefan Schoenfelder & Peter Fraser & Yasuyuki Ohkawa & Hiroshi Kimura & Masako Narita & Masashi Narita, 2024. "HMGA1 orchestrates chromatin compartmentalization and sequesters genes into 3D networks coordinating senescence heterogeneity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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