The Effects of Chromatin Remodeling and Pseudokinase Activity on Liver Pathophysiology

Date

August 2021

Authors

Moore, Austin Bradley

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Abstract

The liver exhibits a remarkable capability to regenerate itself in the face of injury; however, in the setting of sustained damage, this capability can be overwhelmed and eventually lead to chronic liver diseases such as non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Although these processes are complex and not completely understood, specific genetic and epigenetic factors that drive aspects of this pathophysiology can shed further light on both how these diseases develop and on how normal, healthy regeneration differs from liver disease. In this body of work, we show that loss of Arid1a, a DNA-binding component of the SWI/SNF chromatin remodeling complex, shifts hepatocyte metabolism to promote lipid accumulation in a manner similar to that seen in non-alcoholic fatty liver disease. We further explore the dynamics of the SWI/SNF complex by examining a mutually exclusive homolog of Arid1a, Arid1b, and provide evidence to suggest that its role is to stabilize the hepatocyte SWI/SNF complex in the absence of Arid1a seen in regeneration and hepatocellular carcinoma. Finally, we harness the power of in vivo CRISPR screening within the liver to identify the pseudokinase STK31 as a positive regulator of hepatocyte proliferation and liver oncogenesis. Our findings underscore the important role that chromatin remodeling has in enforcing hepatocyte identity and functionality as well as allowing for plasticity. Additionally, our work with STK31 highlights the power of in vivo screening within the liver to identify new potential therapeutic targets not only for hepatocellular carcinoma, but other tumor types as well.

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