Loss of the histone demethylase Phf8 is compatible with development but confers resilience to anxiety and depression

Phf8 is a histone demethylase associated with human developmental disorders and cancer. Early studies of Phf8 in humans indicated that inactivating mutations in the gene were linked to syndromic intellectual disability with cleft lip and palate (Siderius syndrome). However, Phf8's functional role in regulating mammalian development and behavior has not been demonstrated. In this thesis I present my findings on a knockout mouse model of Phf8, which I have generated and characterized to interrogate Phf8's function in these processes in an in vivo mammalian system. Unexpectedly, I did not detect any gross physiological defects nor intellectual disability, but instead report here that mice null for Phf8 are resilient to anxiety and depression. I further characterized the molecular nature of Phf8's role regulating mammalian behavior by performing RNA-seq on regions in the brain key to mediating anxiety disorders and depression. Here I find evidence that Phf8 directly regulates multiple serotonin receptors in the prefrontal cortex, which have a long standing link to anxiety disorders and depression, suggesting a likely mechanism for resiliency.;In addition to its proposed function in behavior and development, multiple studies have implicated Phf8 cancer. It has been suggested that Phf8 can behave as an oncogene, notably in the case of T-ALL, where it cooperates with the Notch pathway and is required to drive tumor proliferation in vitro and in xenograft models. Within this thesis I will also present my findings on Phf8's function in the context of an in vivo model of T-ALL. I do not observe a requirement for Phf8 in T-ALL nor does its loss seem to at all impair the progression of T-ALL driven by a constitutively active Notch1. However, I do observe a subtle defect in T-cell development, which is likely consistent with its function in effecting Notch signaling. The data within this thesis represent the first characterization of a mammalian knockout model of Phf8 and describe a novel role for this gene in the regulation of anxiety and depression.