Sex-Dependent Liver Gene Expression Is Extensive and Largely Dependent upon Signal Transducer and Activator of Transcription 5b (STAT5b): STAT5b-Dependent Activation of Male Genes and Repression of Female Genes Revealed by Microarray Analysis

Clodfelter, Karl H.; Holloway, Minita G.; Hodor, Paul; Park, Soo-Hee; Ray, William J.; Waxman, David J.

doi:10.1210/me.2005-0489

Cited by 223 publications

(295 citation statements)

References 56 publications

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“…In the present study we have characterized bi-directional crosstalk between STAT5b and HNF4α, which both play important roles in liver gene expression, in particular sex-dependent, GHregulated gene expression, as revealed by the analysis of knockout mouse models [6,12,21]. We also demonstrate that STAT5b enhances HNF4α-dependent gene transcription, while HNF4α is shown to inhibit GH-stimulated STAT5b tyrosine phosphorylation, nuclear translocation and transcriptional activity.…”

Section: Discussionmentioning

confidence: 54%

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Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Park

Wiwi

Waxman

2006

Biochemical Journal

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In the present study, we have characterized signalling cross-talk between STAT5b (signal transducer and activator of transcription 5b) and HNF4α (hepatocyte nuclear factor 4α), two major regulators of sex-dependent gene expression in the liver. In a HepG2 liver cell model, HNF4α strongly inhibited β-casein and ntcp (Na + /taurocholate cotransporting polypeptide) promoter activity stimulated by GH (growth hormone)-activated STAT5b, but had no effect on interferon-γ -stimulated STAT1 transcriptional activity. By contrast, STAT5b synergistically enhanced the transcriptional activity of HNF4α towards the ApoCIII (apolipoprotein CIII) promoter. The inhibitory effect of HNF4α on STAT5b transcription was associated with the inhibition of GH-stimulated STAT5b tyrosine phosphorylation and nuclear translocation. The short-chain fatty acid, butyrate, reversed STAT5b transcriptional inhibition by HNF4α, but did not reverse the inhibition of STAT5b tyrosine phosphorylation. HNF4α inhibition of STAT5b tyrosine phosphorylation was not reversed by pervanadate or by dominant-negative phosphotyrosine phosphatase 1B, suggesting that it does not result from an increase in STAT5b dephosphorylation. Rather, HNF4α blocked GHstimulated tyrosine phosphorylation of JAK2 (Janus kinase 2), a STAT5b tyrosine kinase. Thus STAT5b and HNF4α exhibit bidirectional cross-talk that may augment HNF4α-dependent gene transcription while inhibiting STAT5b transcriptional activity via the inhibitory effects of HNF4α on JAK2 phosphorylation, which leads to inhibition of STAT5b signalling initiated by the GH receptor at the cell surface.

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Section: Discussionmentioning

confidence: 54%

“…The importance of this pathway is evident from the characterization of STAT5b-deficient male mice [19,20], which exhibit impaired body growth from approx. 4 weeks of age and a global loss of sex-dependent liver CYP expression [21].…”

Section: Introductionmentioning

confidence: 98%

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Park

Wiwi

Waxman

2006

Biochemical Journal

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“…11 However, it would be simplistic to assume that loss of Stat5 would result in physiological defects that could be explained easily through the deregulation of a limited set of target genes. This study provides evidence that the deletion of Stat5 results in complex molecular and physiological changes that have their roots in part in the aberrant activation of otherwise relatively quiescent signaling pathways (for summary, see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…12 There is extensive overlap between the data from the Stat5b-null mice 11 and the liverspecific Stat5 Ϫ/Ϫ mice reported in this work (see Supplementary Table 1). For example, deregulation of several members of the cytochrome P450 family was concordant in both studies.…”

Section: Molecular Networkmentioning

confidence: 93%

Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration†

et al. 2007

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Growth hormone controls many facets of a cell's biology through the transcription factors Stat5a and Stat5b (Stat5). However, whole body deletion of these genes from the mouse does not provide portentous information on cell-specific cytokine signaling. To explore liver-specific functions of Stat5, the entire Stat5 locus was deleted in hepatocytes using Cre-mediated recombination. Notably, Stat5-mutant mice developed fatty livers and displayed impaired proliferation of hepatocytes upon partial hepatectomy (PHx). Loss of Stat5 led to molecular consequences beyond the reduced expression of Stat5 target genes, such as those encoding suppressor of cytokine signaling 2 (SOCS2), Cish, and insulin-like growth factor 1 (IGF-1). In particular, circulating growth hormone levels were increased and correlated with insulin resistance and increased insulin levels. Aberrant growth hormone (GH)-induced activation of the transcription factors Stat1 and Stat3 was observed in mutant livers. To test whether some of the defects observed in liver-specific Stat5 deficient mice were due to aberrant Stat1 expression and activation, we generated Stat1 ؊/؊ mice with a hepatocyte-specific deletion of Stat5. Mouse genetics has been employed to dissect the degree to which GH signals through its downstream mediators Stat5 and IGF-1. Inactivation of the GHR gene results in severe postnatal growth retardation, greatly decreased levels of IGF-1, and elevated levels of circulating GH. 1,2 The transcription factors Stat5a and Stat5b are highly conserved and serve overlapping and mostly redundant roles. However, pubertal growth of Stat5b Ϫ/Ϫ males, but not females, is reduced. 3,4 In contrast, normal body growth was observed in both Stat5a Ϫ/Ϫ males and females. 4,5 The complete deletion of the entire Stat5a/b locus resulted in perinatal lethality, 6 suggesting that Stat5 has a more important role than previously considered.It can be hypothesized that the loss of Stat5 will alter the physiology of a cell, because it also controls the transcription of genes encoding suppressor of cytokine signaling 2 (SOCS2) and SOCS3, which are negative regulators of cytokine signaling. Moreover, loss of Stat5 would result in vacant recruitment sites on receptors, which could lead to the activation of other STATs and their downstream targets. To further explore the complexity of the GHStat5 regulatory network in liver, we deleted the Stat5 locus specifically in hepatocytes using Cre-mediated re-

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“…The genetic and transcriptional mechanisms regulating differences between the sexes have intensively been investigated in the liver but dimorphic gene expression has also been reported in mouse kidney, blastocysts, lacrimal gland, and brain [2][3][4][5]. A recent microarray analysis of 23,574 transcripts by Yang et al revealed the extent of sexual dimorphism in gene expression to be much greater than previously recognized.…”

Section: Extent Of Global Sexual Dimorphismmentioning

confidence: 99%

Sexual dimorphism in environmental epigenetic programming

Gabory

Attig

Junien

2009

Molecular and Cellular Endocrinology

249

196

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The phenotype of an individual is the result of complex interactions between genotype and current, past and ancestral environment leading to a lifelong remodelling of our epigenomes. The vast majority of common diseases, including atherosclerosis, diabetes, osteoporosis, asthma, neuropsychological and autoimmune diseases, which often take root in early development, display some degree of sex bias, very marked in some cases. This bias could be explained by the role of sex chromosomes, the different regulatory pathways underlying sexual development of most organs and finally, lifelong fluctuating impact of sex hormones. A substantial proportion of dimorphic genes expression might be under the control of sex-specific epigenetic marks. Environmental factors such as social behaviour, nutrition or chemical compounds can influence, in a gender-related manner, these flexible epigenetic marks during particular spatiotemporal windows of life. Thus, finely tuned developmental program aspects, for each sex, may be more sensitive to specific environmental challenges, particularly during developmental programming and gametogenesis, but also throughout the individual's life under the influence of sex steroid hormones and/or sex chromosomes. An unfavourable programming could thus lead to various defects and different susceptibility to diseases between males and females. Recent studies suggest that this epigenetic programming could be sometimes transmitted to subsequent generations in a sex specific manner and lead to transgenerational effects (TGEs).This review summarizes the current understanding in the field of epigenetic programming and highlights the importance of studying both sexes in epidemiological protocols or dietary interventions both in humans and in experimental animal models.

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Sex-Dependent Liver Gene Expression Is Extensive and Largely Dependent upon Signal Transducer and Activator of Transcription 5b (STAT5b): STAT5b-Dependent Activation of Male Genes and Repression of Female Genes Revealed by Microarray Analysis

Cited by 223 publications

References 56 publications

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration†

Sexual dimorphism in environmental epigenetic programming

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