The retrotransposon gag domain containing protein Rgag4 is an Ikaros target in the pituitary

Previous studies have established the common and critical involvement of the zinc finger protein Ikaros in lymphoid and pituitary cell development and expansion. Key to the assembly of several transcriptional networks, we have demonstrated up-regulation of Ikaros and its interacting partner the C-terminal Binding Protein (CtBP) in response to hypoxia. This prompted us to explore common transcriptional targets using a chromatin immunoprecipitate (ChIP) screen of DNA from pituitary corticotroph cells. This strategy yielded a finite list of targets common to both transcription factors that included the metalloprotease ADAMTS10. In this report, we focus on validation of a second candidate target, the retrotransposon gag domain containing protein Rgag4. We identified the ability of Ikaros to bind the Rgag4 promoter, influence its transcriptional activity, and induce endogenous gene expression. Robust expression of Rgag4 was noted in the anterior lobe of the pituitary gland which was diminished in Ikaros knockout mice. Down-regulation of Rgag4 resulted in profound reduction of hormone gene expression with diminished ACTH secretion, recapitulating the effect of Ikaros deficiency in knockout mice. The results introduce Rgag4 to the repertoire of effectors serving to couple the chromatin remodeler Ikaros with the hormonal stress response.