期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-04283-9
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资金
- University of Cambridge
- Cancer Research UK
- Hutchison Whampoa
- Cancer Research UK Cambridge Institute Core Grant [C14303/A17197]
- Cancer Research UK Early Detection Pump Priming award [C20/A20976]
- Medical Research Council [MR/M013049/1]
- Tokyo Tech World Research Hub Initiative (WRHI)
- CRUK Clinician Scientist Fellowship [C52489/A19924]
- EMBO
- Medical Research Council
- JSPS KAKENHI [JP25116005, JP26291071, 15K21730, 17H01417]
- MRC [MR/R010013/1, MR/R001146/1, MC_UU_12022/10, MR/M013049/1] Funding Source: UKRI
- Cancer Research UK [15890, 24453, 19924] Funding Source: researchfish
- Medical Research Council [MC_UU_12022/10, MR/M013049/1, MR/R001146/1, MR/R010013/1] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [15K21730, 26291071, 25116005, 17H01417] Funding Source: KAKEN
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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