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In Vivo Transcript Profiling and Phylogenetic Analysis Identifies Suppressor of Cytokine Signaling 2 as a Direct Signal Transducer and Activator of Transcription 5b Target in Liver

Department of Molecular Medicine and Surgery (O.M.V., R.M., E.R.-B., G.N., A.F.-M.), Karolinska Institutet, 17176 Stockholm, Sweden; Molecular Endocrinology Group (L.F.-P.), Department of Clinical Sciences, University of Las Palmas de Gran Canaria, 35011 Las Palmas de Gran Canaria, Spain; Department of Biochemistry and Molecular Biology (D.J.C., J.W., M.O.), Oregon Health & Science University, Portland, Oregon 97239-3098; and Computational Biology Unit (B.L.), Bergen Centre for Computational Science, University of Bergen, N-5008 Bergen, Norway

Address all correspondence and requests for reprints to: Amilcar Flores-Morales, Center of Molecular Medicine (CMM), L8:01, Karolinska Hospital, 17176 Stockholm, Sweden. E-mail: Amilcar.Flores{at}ki.se.

ABSTRACT

The GH-activated signal transducer and activator of transcription 5b (STAT5b) is an essential regulator of somatic growth. The transcriptional response to STAT5b in liver is poorly understood. We have combined microarray-based expression profiling and phylogenetic analysis of gene regulatory regions to study the interplay between STAT5b and GH in the regulation of hepatic gene expression. The acute transcriptional response to GH in vivo after a single pulse of GH was studied in the liver of hypophysectomized rats in the presence of either constitutively active or a dominant-negative STAT5b delivered by adenoviral gene transfer. Genes showing differential expression in these two situations were analyzed for the presence of STAT5b binding sites in promoter and intronic regions that are phylogenetically conserved between rats and humans. Using this approach, we showed that most rapid transcriptional effects of GH in the liver are not results of direct actions of STAT5b. In addition, we identified novel STAT5b cis regulatory elements in genes such as Frizzled-4, epithelial membrane protein-1, and the suppressor of cytokine signaling 2 (SOCS2). Detailed analysis of SOCS2 promoter demonstrated its direct transcriptional regulation by STAT5b upon GH stimulation. A novel response element was identified within the first intron of the human SOCS2 gene composed of an E-box followed by tandem STAT5b binding sites, both of which are required for full GH responsiveness. In summary, we demonstrate the power of combining transcript profiling with phylogenetic sequence analysis to define novel regulatory paradigms.

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