Genome-wide analysis reveals roles of the transcriptional repressor Bcl6 in Growth Hormone action

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 88-108-GHRH, GH & IGF Biology & Signaling
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-97
Jessica Schwartz*1, Grace Lin2, Christopher Ryan Lapensee2, Jennifer Harley2, Jeffrey S Huo2, Richard McEachin2, Zhaohui Steve Qin3 and Rajasree Menon2
1Univ of Michigan Med Sch, Ann Arbor, MI, 2University of Michigan, Ann Arbor, MI, 3Emory University, Atlanta, GA
In a profile of genes regulated by GH we found that the gene encoding the transcriptional repressor B-cell lymphoma 6 (Bcl6) was highly repressed by chronic GH in 3T3-F442A adipocytes.  Further, levels of Bcl6 mRNA are decreased by GH in fat and liver cells in vitro, and in multiple tissues of mice chronically treated with GH.  For insight into the roles of genes regulated by Bcl6 in GH action, we used chromatin immunoprecipitation (ChIP) with anti-Bcl6, followed by deep sequencing (ChIP-Seq), and identified over 3000 sequences occupied by endogenous Bcl6 throughout the mouse genome.  Consensus motifs for binding of Bcl6 and of Stat5, a GH-activated transcription factor, were highly represented in occupied sequences.  Insulin signaling and Diabetes Mellitus Type 2 were among the most highly represented pathways, suggesting that Bcl6 may be implicated in insulin resistance, a known consequence of chronic GH excess.  Gene Ontology analysis of genes near sequences occupied by Bcl6 identified biological processes related to lipid metabolism as top categories.  Computationally comparing Bcl6-occupied genes with the profile of GH-regulated genes identified subsets of Bcl6 target genes which increased or decreased with GH.  Suppressor of Cytokine Signaling 2 (Socs2) was the most significantly increased gene in response to GH and was found to be repressed by Bcl6 overexpression in vitro.  Among the novel Bcl6/GH target genes, we found that the gene encoding Angiotensinogen (Agt) was stimulated by GH in fat and liver in vitro and in vivo.  ChIP showed that Agt DNA is occupied by Bcl6 and Stat5, which bind to similar sequence motifs.  Agt activation was found to be inhibited by Bcl6 and stimulated by Stat5.  In addition to its established role in the Renin-Angiotensin System regulating blood pressure, Agt has been implicated in adipocyte metabolism and in regulating insulin responsiveness.  Taken together, analysis of Bcl6 target genes identified by ChIP-Seq has revealed potential regulatory mechanisms involving Bcl6 that are related to GH-induced insulin resistance and other responses to GH.

Nothing to Disclose: JS, GL, CRL, JH, JSH, RM, ZSQ, RM

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