There is incomplete understanding of liver cirrhosis pathogenesis and how it might be modulated. We recently discovered that Arid1a, a component of the SWI/SNF ATP-dependent chromatin-remodeling complex, plays potent roles in liver injury and regeneration. We found that liver-specific Arid1a knockout mice are highly resistant to liver damage and fibrosis after multiple forms of chemical injury. These mice also have faster regeneration after partial hepatectomy. Arid1a deficient livers show suppressed terminal differentiation and increased proliferation after injuries, leading to more rapid and complete tissue repair, and in some cases improved survival. Mice with whole-body Arid1a deficiency exhibit improved soft tissue and pancreatic ?-cell regeneration. These findings for the first time connect chromatin-remodeling machinery with tissue repair and organ regeneration. This also suggests the existence of regeneration suppressor genes (analogous to tumor suppressors), that when repressed or lost, promote tissue repair in the context of chronic liver disease. Given that the loss of Arid1a from SWI/SNF chromatin-remodeling complexes improved hepatocyte fitness after diverse injuries, our central hypothesis is that epigenetic changes have a major impact on tissue damage and repair in cirrhosis progression and could be exploited for therapy. Several critical aspects of this hypothesis demand further investigation.
In AIM 1, we will biochemically characterize SWI/SNF complexes and how they influence their genomic targets in the presence and absence of Arid1a.
In AIM 2, we will determine if mutations in chromatin-remodeling genes such as ARID1A appear in non-malignant human liver disease tissues. We will then assess the functional impact of inactivating mutations in mouse models of chronic liver disease progression.
In AIM 3, we will determine if Arid1b, a closely related paralog that has been observed to structurally substitute for Arid1a within complexes, is a functional antagonist of Arid1a, and is thus responsible for enhancing regeneration in gain and loss-of-function mouse models. Addressing these major questions with biochemical, cellular, and genetic approaches will increase our understanding of how the SWI/SNF complex influences organ regeneration and liver disease pathogenesis. Although it is not currently known if the suppression of ARID1A or activation of ARID1B will be practical in a therapeutic sense, knowledge gained in this area may one day lead to novel strategies to counteract or reverse the development of cirrhosis.
Severe chronic insults can outstrip the potent healing abilities of the liver and ultimately lead to liver damage and cirrhosis. Loss of the epigenetic regulator Arid1a from SWI/SNF chromatin-remodeling complexes results in improved liver fitness after diverse surgical and chemical injuries. We will investigate how SWI/SNF regulates liver tissue homeostasis with biochemical, cellular, and mouse genetic approaches. Knowledge gained from this study could lead to a better understanding of how cirrhosis develops.
|Sun, Xuxu; Wang, Sam C; Wei, Yonglong et al. (2018) Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer. Cancer Cell 33:151-152|
|Zhang, Shuyuan; Nguyen, Liem H; Zhou, Kejin et al. (2018) Knockdown of Anillin Actin Binding Protein Blocks Cytokinesis in Hepatocytes and Reduces Liver Tumor Development in Mice Without Affecting Regeneration. Gastroenterology 154:1421-1434|
|Sun, Xuxu; Wang, Sam C; Wei, Yonglong et al. (2017) Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer. Cancer Cell 32:574-589.e6|