This Article Full Text Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, Y. Articles by Schwartz, J. Search for Related Content PubMed PubMed Citation Articles by Chen, Y. Articles by Schwartz, J.

Computational and Functional Analysis of Growth Hormone (GH)-Regulated Genes Identifies the Transcriptional Repressor B-Cell Lymphoma 6 (Bc16) as a Participant in GH-Regulated Transcription

Bioinformatics Program (Y.C., D.J.S., Z.S.Q., J.S.), Program in Cellular and Molecular Biology (G.L., J.S.H., J.S.), and Departments of Molecular and Integrative Physiology (D.B., Z.W., T.L., J.S.), Human Genetics (D.J.S.), and Biostatistics (Z.S.Q.), University of Michigan, Ann Arbor, Michigan 48109-5622

Address all correspondence and requests for reprints to: Jessica Schwartz, Ph.D., Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109-5622. E-mail: jeschwar{at}umich.edu.

For insight into transcriptional mechanisms mediating physiological responses to GH, data mining was performed on a profile of GH-regulated genes induced or inhibited at different times in highly responsive 3T3-F442A adipocytes. Gene set enrichment analysis indicated that GH-regulated genes are enriched in pathways including phosphoinositide and insulin signaling and suggested that suppressor of cytokine signaling 2 (SOCS2) and phosphoinositide 3' kinase regulatory subunit p85 (Pik3r1) are important targets. Model-based Chinese restaurant clustering identified a group of genes highly regulated by GH at times consistent with its key physiological actions. This cluster included IGF-I, phosphoinositide 3' kinase p85, SOCS2, and cytokine-inducible SH2-containing protein. It also contains the most strongly repressed gene in the profile, B cell lymphoma 6 (Bcl6), a transcriptional repressor. Quantitative real-time PCR verified the strong decrease in Bcl6 mRNA after GH treatment and induction of the other genes in the cluster. Transcriptional network analysis of the genes implicated signal transducer and activator of transcription (Stat) 5 as hub regulating the most responsive genes, Igf1, Socs2, Cish, and Bcl6. Transcriptional activation analysis demonstrated that Bcl6 inhibits SOCS2-luciferase and blunts its stimulation by GH. Occupancy of endogenous Bcl6 on SOCS2 DNA decreased after GH treatment, whereas occupancy of Stat5 increased concomitantly. Thus, GH-mediated inhibition of Bcl6 expression may reverse the repression of SOCS2 and facilitate SOCS2 activation by GH. Together these analyses identify Bcl6 as a participant in GH-regulated gene expression and suggest an interplay between the repressor Bcl6 and the activator Stat5 in regulating genes, which contribute to GH responses.

This article has been cited by other articles:

				R. D. Meyer, E. V. Laz, T. Su, and D. J. Waxman Male-Specific Hepatic Bcl6: Growth Hormone-Induced Block of Transcription Elongation in Females and Binding to Target Genes Inversely Coordinated with STAT5 Mol. Endocrinol., November 1, 2009; 23(11): 1914 - 1926. [Abstract] [Full Text] [PDF]