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

Aled J Parry,Masashi Narita,Dóra Bihary,Kosuke Tomimatsu,Amy Smith,Robert Hänsel-Hertsch,Shankar Balasubramanian,I Alasdair Russell,Shamith A Samarajiwa,Stephen Smith,Paula D’Santos,Matthew Hoare,Hiroshi Kimura,Elizabeth Mannion

doi:10.1038/s41467-018-04283-9

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.

Highlights

Senescent cells interact with the surrounding microenvironment achieving diverse functional outcomes
We have previously demonstrated that ectopic NOTCH1-intracellular domain (N1ICD), an active form of NOTCH1 (Fig. 1a), can drive NOTCH-induced senescence (NIS) that is distinct from RAS-induced senescent (RIS) in terms of SASP composition[9] and noticed that NIS cells have a unique chromatin structure
Using magnetic-activated cell sorting (MACS) peak calling, we found that the number of peaks identified in each replicate of a condition was similar and that, in general, chromatin accessibility was dramatically increased in RIS (145,649 consensus peaks detected in ≥2 replicates) and NIS cells (149,877 peaks) relative to growing cells (83,920 peaks) (Supplementary Fig. 5a)

Summary

Introduction

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 upregulating the NOTCH ligand JAG1. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells exhibit a massive increase in chromatin accessibility. Persistent cell cycle arrest is accompanied by diverse transcriptional, biochemical and morphological alterations These senescence hallmarks include increased expression and secretion of soluble factors (senescence-associated secretory phenotype (SASP))[2,3] and dramatic alterations to chromatin structure[1,4,5]. We showed that during NIS there is a dramatic and specific upregulation of JAG1 that can activate NOTCH1 signalling and drive NIS in adjacent cells (‘lateral induction’)[9]. In oncogenic RAS-induced senescent (RIS) fibroblasts, characteristic changes to chromatin culminate in the formation of senescence-associated heterochromatic foci (SAHFs)[13], layered structures facilitated by spatial

Methods

Results

Conclusion