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Elucidating the role of Arid1a in adult liver

Periodic Reporting for period 1 - EPILIPRO (Elucidating the role of Arid1a in adult liver)

Reporting period: 2016-05-01 to 2018-04-30

This work aims to identify molecular mechanisms governing adult ductal progenitors. Ductal progenitors play a crucial role in liver regeneration (Miyajima et al., Cell Stem Cell 2014; Aloia et al., J Physiol, 2016; Raven et al, Nature 2017). Defective regenerative processes mediated by liver progenitors are involved in liver disease (Libbrecht et al., Seminars in Cell & Developmental Biology, 2002). Cirrhosis and liver cancer are common diseases especially in people aged sixty or older and their rates have risen considerably in the past decades, probably to increased alcohol intake and obesity rate. However, the molecular mechanisms behind response to damage of the liver are still largely unknown. In this light, this work aims to propose novel therapeutic targets in order to promote liver regeneration.
This work has elucidated key epigenetic mechanisms governing adult ductal liver progenitors. More in detail, I found that the epigenetic factors Arid1a and Tet1 plays a crucial role in liver progenitors. Interestingly, Tet1 promotes liver regeneration whereas Arid1a depletion facilitates proliferation of liver regeneration. Altogether I identified and characterised novel epigenetic mechanisms involved in liver regeneration mediated by liver progenitors, opening new avenues for therapy promoting liver regeneration. Altogether I identified and characterised novel epigenetic mechanisms involved in liver regeneration mediated by liver progenitors, opening new avenues for therapy promoting liver regeneration. I presented my work at several local meetings (internal seminars in the Institute, Cambridge Stem Cell Club, Cambridge Epigenetic Symposium 2016 and 2017, PDN symposium 2018), international conferences (ISSCR meeting in Boston 2017 and Novo Nordisk Stem Cell Niche meeting in Copenhagen 2018) and workshops in Cambridge (UK), Barcelona (Spain) and Seoul (South Korea). Moreover, I was able to present this work to a general audience by joining the Creative Climate Change Symposium at Birbeck University in London and Creative Reactions, Pint of Science in Cambridge in 2018.
This project has identified novel players involved in liver regeneration, thus opening new avenues for therapy of liver disease, which is becoming of great concern. For instance the most common chronic disease, non-alcoholic fatty liver disease affects from 14 to 27% of the general population in the industrial world (Weiß et al, 2014). Moreover, in the UK, since 1990, liver cancer incidence rates have increased by around 151% according to Cancer Research UK. This project takes advantage of state-of-art technologies such as 3D organoid cultures and elucidates novel mechanisms, which can improve this technology. Also, very advanced single cell technologies have been employed and the upcoming results will constitute an important step in order to widely use these new methods.
The project shows a role for Tet and Arid1a in liver progenitor in vivo and in vitro