Antagonism in Growth Hormone Signaling in Muscle by BCL6

BCL6 is a sequence-specific DNA binding factor that represses transcription via interactions with various co-repressors. Importantly, the BCL6 repressor binds to consensus DNA sequences that may be alternatively bound and transcriptionally activated by STAT proteins such as STAT5, a primary transcriptional effector of GH-induced signaling. Thus, I hypothesize that disruption of BCL6 in skeletal muscle will mimic the effects of growth hormone through unopposed transcriptional de-repression of BCL6Stat5 co-regulated enhancers and promoters. To test this, I will use next-generation sequencing to define the BCL6 and STAT5 gene regulatory networks in skeletal muscle tissue in vivo and in vitro. Additionally, I will use BCL6 tissue-specific knockout mice to determine the impact of BCL6 on GH-controlled muscle physiology, including muscle lipid metabolism, growth, fiber type composition, body composition, and insulin sensitivity. Together, these studies will establish a framework for epigenetic regulation of the GH gene network in muscle and elucidate the role for BCL6 as a physiologic antagonist of growth hormone, thus providing a springboard for future therapeutic discovery.