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bioRxiv · 10.1101/212829

NOTCH-mediated non-cell autonomous regulation of chromatinstructure during senescence

Parry, A. J.·Hoare, M.·Bihary, D.·Hänsel-Hertsch, R.·Smith, S.·Tomimatsu, K.·Balasubramanian, S.·Kimura, H.·Samarajiwa, S.·Narita, M.
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Abstract

Senescent cells interact with the surrounding microenvironment achieving diverse functional outcomes. In addition to autocrine and paracrine signalling mediated by factors of the senescence-associated secretory phenotype, we have recently identified that NOTCH1 can drive lateral induction of a unique form of senescence in adjacent cells through specific induction of the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure both autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells in culture exhibit a massive increase in nucleosome-free regions (NRFs). NOTCH signalling suppresses both SAHF and NFR formation in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, also 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 a range of human cancers. Thus, HMGA1 is involved not only in SAHFs, but also RIS-specific NFR formation. In conclusion, this study identifies that the JAG1-NOTCH-HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.

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Parry, A. J., Hoare, M., Bihary, D., Hänsel-Hertsch, R., Smith, S., Tomimatsu, K., Balasubramanian, S., Kimura, H., Samarajiwa, S., Narita, M.. 2017-11-02. NOTCH-mediated non-cell autonomous regulation of chromatinstructure during senescence. https://doi.org/10.1101/212829

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