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

Vidal, Oscar M.; Merino, Roxana; Rico-Bautista, Elizabeth; Fernández-Pérez, Leandro; Chia, Dennis J.; Woelfle, Joachim; Ono, M.; Lenhard, Boris; Norstedt, Gunnar; Rotwein, Peter; Flores‐Morales, Amilcar

doi:10.1210/me.2006-0096

Cited by 69 publications

(71 citation statements)

References 65 publications

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“…This interaction was shown to be critical for the regulation of specific subsets of metabolic genes (24). (69) analyzed gene expression profiles in liver tissue from mice that carry truncated GHRs that impair STAT5A/B signaling, and Vidal et al (84) analyzed gene expression in mice on GH stimulation. On the basis of these experiments, a large set of genes was identified whose expression was altered on the deletion of STAT5A/B.…”

Section: Cytokine-stat5a/b Signaling In the Livermentioning

confidence: 99%

Genomic dissection of the cytokine-controlled STAT5 signaling network in liver

Hosui

Hennighausen

2008

Physiological Genomics

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Hosui A, Hennighausen L. Genomic dissection of the cytokine-controlled STAT5 signaling network in liver. Physiol Genomics 34: 135-143, 2008. First published May 6, 2008 doi:10.1152/physiolgenomics.00048.2008.-Growth hormone (GH) controls the physiology and pathophysiology of the liver, and its signals are conducted by two members of the family of signal transducers and activators of transcription, STAT5A and STAT5B. Mice in which the Stat5a/b locus has been inactivated specifically in hepatocytes display GH resistance, the sex-specific expression of genes associated with liver metabolism and the cytochrome P-450 system is lost, and they develop hepatosteatosis. Several groups have shown by global gene expression profiling that a cadre of STAT5A/B target genes identify genetic cascades induced by GH and other cytokines. Evidence is accumulating that in the absence of STAT5A/B GH aberrantly activates STAT1 and STAT3 and their downstream target genes and thereby offers a partial explanation of some of the physiological alterations observed in Stat5a/b-null mice and human patients. We hypothesize that phenotypic changes observed in the absence of STAT5A/B are due to two distinct molecular consequences: first, the failure of STAT5A/B target genes to be activated by GH and second, the rerouting of GH signaling to other members of the STAT family. Rerouting of GH signaling to STAT1 and STAT3 might partially compensate for the loss of STAT5A/B, but it certainly activates biological programs distinct from STAT5A/B. Here we discuss the extent to which studies on global gene expression profiling have fostered a better understanding of the biology behind cytokine-STAT5A/B networks in hepatocytes. We also explore whether this wealth of information on gene activity can be used to further understand the roles of cytokines in liver disease.signal transducers and activators of transcription; knockout; metabolism THE ABILITY TO MUTATE individual genes in the mouse has permitted detailed studies on their roles in development, physiology, and disease. In particular, gene knockout mice have provided in-depth insight into the molecular structure and dynamics of signal transduction networks. However, in many cases the physiological consequences observed in mutant mice, or lack thereof, were unexpected and irreconcilable with the proposed functions of the protein under investigation. Genomewide gene expression profiling from gene knockout mice should provide an inroad into better understanding of the molecular consequences of disrupting complex information networks. The application of global approaches to the analysis of complex biological systems including organ development, physiology, and disease has gained considerable strength. Characterization of molecular networks that drive these biological processes has been facilitated by the emergence of affordable high-throughput technologies, including DNA microarrays that can monitor the activity of an entire genome. Such approaches have the promise to facilitate an understanding of mole...

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Section: Cytokine-stat5a/b Signaling In the Livermentioning

confidence: 99%

Genomic dissection of the cytokine-controlled STAT5 signaling network in liver

Hosui

Hennighausen

2008

Physiological Genomics

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“…Global gene expression analysis has identified many genes that respond to GH rapidly, several of which are known to be direct targets of STAT5 (60)(61)(62). These early GH response genes include several transcription factors that show sex-biased expression.…”

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confidence: 99%

Dynamic, Sex-Differential STAT5 and BCL6 Binding to Sex-Biased, Growth Hormone-Regulated Genes in Adult Mouse Liver

Zhang

Laz

Waxman

2012

Molecular and Cellular Biology

149

261

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Sex-dependent pituitary growth hormone (GH) secretory patterns determine the sex-biased expression of >1,000 genes in mouse and rat liver, affecting lipid and drug metabolism, inflammation, and disease. A fundamental biological question is how robust differential expression can be achieved for hundreds of sex-biased genes simply based on the GH input signal pattern: pulsatile GH stimulation in males versus near-continuous GH exposure in females. STAT5 is an essential transcriptional mediator of the sex-dependent effects of GH in the liver, but the mechanisms that underlie its sex-dependent actions are obscure. Here we elucidate the dynamic, sex-dependent binding of STAT5 and the GH/STAT5-regulated repressor BCL6 to mouse liver chromatin genome wide, revealing a counteractive interplay between these two regulators of sex differences in liver gene expression. Our findings establish a close correlation between sex-dependent STAT5 binding and sex-biased target gene expression. Moreover, sex-dependent STAT5 binding correlated positively with sex-biased DNase hypersensitivity and H3-K4me1 and H3-K4me3 (activating) marks, correlated negatively with sex-biased H3-K27me3 (repressive) marks, and was associated with sexdifferentially enriched motifs for HNF6/CDP factors. Importantly, BCL6 binding was preferentially associated with repression of female-biased STAT5 targets in male liver. Furthermore, BCL6 and STAT5 common targets but not BCL6 unique targets showed strong enrichment for lipid and drug metabolism. These findings provide a comprehensive, genome-wide view of the mechanisms whereby these two GH-regulated transcription factors establish and maintain sex differences affecting liver physiology and disease. The approaches used here to characterize sex-dependent STAT5 and BCL6 binding can be applied to other condition-specific regulatory factors and binding sites and their interplay with cooperative chromatin binding factors.

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“…Given that the fish embryos undergo dynamic cell movement in early development, e.g., gastrulation movements (Chen et al 2009), it is possible that the GH/GHR pathway may participate in the regulation of cell movement during early development. It was also reported that GH/Stat5b can directly regulate the transcription of a Wnt signaling element (frizzled4) and suppressors of cytokine signaling (Vidal et al 2007), thus it is also possible that GH/GHR pathway may crosstalk with the other pathways to regulate the early development of fish.…”

Section: Discussionmentioning

confidence: 99%