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  3. Narita Group

Research Summary

We study how stress affects our cells, causing them to age and stop working properly. Our DNA, which contains our genetic information, can get damaged over time due to aging or UV light, making cells stop functioning as they should. These aged cells, known as senescent cells, no longer help repair our bodies. We aim to understand how this process works, including how DNA organisation affects cell changes, how certain genes linked to cancer cause cells to age, and how the buildup of these aged cells over time leads to aging.

Introduction

Senescence is a state of persistent cell cycle arrest triggered by various stimuli but senescent are not inert. Rather they actively communicate with their surroundings, shaping the tissue microenvironment and potentially burdening the individual, especially in aging but also in cancer. We are particularly interested in understanding what senescent cells do to tissues and how they achieve such altered functionality. 

Professor Masashi Narita

Senior Group Leader

Focus areas

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High-order chromatin organisation

Our group studies the global chromatin reorganisation which often accompanies senescence, marked by the formation of senescence-associated heterochromatin foci (SAHFs, Narita et al. Cell 2003). The senescence model we focus on is oncogene-induced senescence (OIS), though we often include comparisons to replicative and DNA-damage induced senescence. SAHF formation is a multifactorial process involving the High Mobility Group A (HMGA) proteins and disruption of the Lamin B1 chromatin tethering at the nuclear periphery. During SAHF-formation, chromatin is organised into concentric epigenetic layers with H3K9m3-core with H3K27me3-shell, excluding euchromatin regions (Chandra et al. Mol Cell 2012). See our recent review article on this topic (Olan, Handa and Narita, Curr. Opinion in Cell Biol. 2023). Recently, we showed that HMGA1 affects chromatin organisation beyond its effect on SAHF, strengthening compartmentalisation (Olan, Ando-Kuri and Parry et al. 2024,  Research Square Preprint). HMGA1 mobilises chromatin depending on the levels of HMGA1 binding, leading to gene repositioning corelated with up- and down-regulation of key senescence genes. Future directions include elucidating nuances of the function of HMGA1 towards chromatin organisation and gene regulation depending on protein modifications and protein binding partners. 

Chromatin reorganisation during senescence is also associated with SAHF-dependent desilencing of ‘lineage-inappropriate’ genes from H3K9me3 heterochromatin primarily at peri-SAHF regions (Tomimatsu et al. Nat Aging 2022), raising important questions about the shift in cell identity. The genes contributing to the senescence-associated secretory phenotype (SASP) often show tissue specificity. See our recent review article on this topic (Olan and Narita. Annu. Rev. Cell Dev. Biol. 2022). SASP is also supported by chromatin loops rewiring due to loss cohesin binding as well as the formation of transcription-dependent cohesin islands (Olan et al. Nat Comm 2020). Our future work aims to integrate the chromatin changes observed during senescence from small scale (loops and enhancer-promoter interactions) to large scale organisation between domains located megabases apart on the linear genome. 

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Titration of oncogenic RAS

Our RAS dose-titrating systems model a non-linear oncogene-induced senescence (OIS) spectrum, including senescence-intermediates such as immune-resistant tumour initiating states, characterised by increased progenitor features and a reduced Myc signature. Moreover, our study uncovers a RAS-dose-associated evolution of senescence and its immune-microenvironment, revealing at least two distinct paths towards tumorigenesis in the liver: 1) a Dlk1/Afp-branch, corresponding to differentiated HCCs with longer latency and 2) a Notch1/Tgfb1/Nes-branch, corresponding to undifferentiated tumours, associated with short latency and poor prognosis. 

Chan et al. 2024. Nature. In Press. 

(Pre-print: https://doi.org/10.21203/rs.3.rs-2842963/v1) 

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Age-associated spontaneous cancer mouse model

We have shown the functional relevance of autophagy in senescence (Young, Narita et al. Genes Dev 2009, Narita, Young et al. Science 2011). To further extend these in vitro studies, we have generated RNAi based autophagy mouse models, where we can switch on/off autophagy using Doxycycline (Dox) -inducible sh-Atg5 (Cassidy, Young, Pérez-Mancera et al. Autophagy 2018). They are hypomorphic and also allow for temporospatial regulation of autophagy without any confounding effects on development. We genetically validated a long-standing question: in mammals does the autophagy-decline induce premature ageing? Indeed, this was the case. Moreover, restoration of autophagy led to a dramatic age reversal, however this was associated with a dramatic increase in tumorigenesis (Cassidy et al. Nat Commun 2020). Our model therefore provides a platform for investigating age-associated tumorigenesis. See our review article on this topic (Cassidy and Narita. Mol. Oncol. 2022) 

Group members

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    Masashi Narita

    Group Leader

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    Masako Narita

    Principal Scientific Associate

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    Andrew Young

    Principal Scientific Associate

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    Adelyne Chan

    Research Associate

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    Ioana Olan

    Research Associate

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    Yongmin Kwon

    Postgraduate Student

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    Tetsuya Handa

    Postgraduate Student

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    Haoran Zhu

    Research Associate