TY - JOUR
T1 - NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence
AU - Parry, Aled J.
AU - Hoare, Matthew
AU - Bihary, Dóra
AU - Hänsel-Hertsch, Robert
AU - Smith, Stephen
AU - Tomimatsu, Kosuke
AU - Mannion, Elizabeth
AU - Smith, Amy
AU - D'Santos, Paula
AU - Russell, I. Alasdair
AU - Balasubramanian, Shankar
AU - Kimura, Hiroshi
AU - Samarajiwa, Shamith A.
AU - Narita, Masashi
N1 - Funding Information:
We thank all members of the Narita laboratory for helpful discussions, M. de la Roche for reagents and staff of the Cancer Research UK Cambridge Institute core facilities for technical support. The University of Cambridge, Cancer Research UK and Hutchison Whampoa supported this work. M.N., S.B. and I.A.R laboratories are funded by a Cancer Research UK Cambridge Institute Core Grant (C14303/A17197). M.N. is also supported by a Cancer Research UK Early Detection Pump Priming award (C20/A20976), Medical Research Council (MR/M013049/1) and Tokyo Tech World Research Hub Initiative (WRHI). M.H. is supported by a CRUK Clinician ScientistFellowship (C52489/A19924). R.H.-H. is funded by an EMBO Long-Term fellowship. S.A.S. and D.B. were supported by Medical Research Council core funding. H.K. was supported by JSPS KAKENHI JP25116005, JP26291071, 15K21730 and 17H01417.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-04283-9
DO - 10.1038/s41467-018-04283-9
M3 - Article
C2 - 29743479
AN - SCOPUS:85046843913
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1840
ER -
