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Zhx2: a potential regulator of sex‐biased liver gene expression

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is the third leading cause of cancer death overall. In addition, males are known to be more susceptible to HCC. Our lab primarily focuses on genetic regulation within the liver and how dysregulation of particular genes contribute to liver development and disease. We identified a novel regulator of gene expression, Zinc Fingers and Homeoboxes 2 (Zhx2), that has been shown to have potential transcriptional and post‐transcriptional mechanisms of regulation. All previously identified Zhx2 targets, including alpha‐fetoprotein (AFP), H19, and Glypican 3 (Gpc3), are dysregulated in HCC. In order to understand the contribution of Zhx2 to global gene regulation during liver development and disease, our lab developed hepatocyte‐specific and whole body Zhx2 knockout (Zhx2ΔHep and Zhx2−) mice. Using these mouse models, we identified dysregulation of a subset of cytochrome p450 enzymes (CYPs) and sex‐limited protein (C4‐Slp), genes that are well‐known to be expressed in a gender‐biased pattern within the liver. Specifically, the absence of Zhx2 in hepatocytes leads to increased expression of female‐specific CYPs and a decreased expression of C4‐Slp in male mice. Curiously, the majority of female‐specific CYPs that we have identified to be upregulated in the absence of Zhx2, are also upregulated in Stat5b knockout male mice, suggesting there may be a connection between Zhx2 and a previously characterized gender‐specific gene expression control pathway. My central hypothesis is that Zhx2 contributes to sexual‐dimorphic patterns of gene expression in the liver. Currently, we are designing experiments to test how Zhx2 regulates sex‐biased genes in the liver, and whether Zhx2 acts in coordination with previously known male‐biased transcriptional regulators such as Bcl6 and Stat5b. Understanding the role of Zhx2 in gender‐biased gene expression may lead to new insights into the basis for HCC predominance in males.