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Autonomous and non-autonomous regulation of chromatin structure during cellular senescence 10.17863/CAM.21001 Parry, Aled John 0000000151923727 Narita, Masashi Senescent cells interact with the surrounding microenvironment achieving both pro- oncogenic and tumour-suppressive outcomes. In addition to autocrine and paracrine signalling mediated by factors of the senescence-associated secretory phenotype (SASP), we have recently identified that NOTCH1 can drive a unique form of senescence in adjacent cells via juxtacrine signalling. Here, we show that NOTCH1 signalling confers a dramatic impact on chromatin structure during senescence. RAS-induced senescent (RIS) fibroblasts often develop chromatin structures called senescence-associated heterochromatic foci (SAHF). We find that NOTCH1 inhibits SAHF formation at least partially through transcriptional repression of a critical structural component, high-mobility group A (HMGA). Using ATAC-sequencing (assay for transposase accessible chromatin) we demonstrate that nucleosome positioning is substantially altered in RIS and that this re-distribution is also antagonised by NOTCH1, resulting in a distinct chromatin landscape. Importantly, normal or cancer cells that express the NOTCH ligand jagged-1 can drive similar chromatin structural changes in adjacent cells in a cell-cell contact dependent manner. In addition, using a highly optimised chromatin immunoprecipitation (ChIP-seq) protocol and the proximity ligation assay ‘Hi-C’, we demonstrate that HMGA proteins are directly involved in the formation of long-range interactions in RIS cells that may underpin SAHF formation. These ChIP-seq data have also allowed us to identify a unique HMGA1 binding profile, potentially suggesting a novel role for HMGA1 in gene regulation. Together, our data indicate that NOTCH signalling, both cell-autonomously and non-cell-autonomously, can repress HMGA1, a multi-faceted protein that regulates nucleosome positioning (1D structure), SAHF formation (3D structure) and potentially mRNA abundance. University of Cambridge 2018-04-07 Thesis Doctoral Doctor of Philosophy (PhD) en Cancer Research UK https://www.repository.cam.ac.uk/handle/1810/273926 controlled.access https://www.repository.cam.ac.uk/bitstreams/02a56cce-b03b-4aed-b54a-542992588696/download f4916d0a78a4e85536a442a34676143c https://www.repository.cam.ac.uk/bitstreams/59939a08-5377-486b-9a90-92ab055cb8ac/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ Chromatin Senescence Cell Biology Genetics Epigenetics Epigenome Cancer Hi-C Interactome ChIP HMGA SAHF NOTCH NOTCH1 JAGGED1