Growth hormone: a newly identified developmental organizer

Das, Rajat K.; Banerjee, Soumya; Shapiro, Barry A.

doi:10.1530/joe-16-0471

Cited by 8 publications

(29 citation statements)

References 54 publications

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“…Consistent with this proposal, male and female livers show intrinsic differences in responsiveness when plasma GH pulses are given to hypophysectomized mice ( 22 ), and primary female rat hepatocyte cultures show greater intrinsic responsiveness to cGH than male hepatocytes ( 59 ). In the rat model, pulsatile GH exposure of male liver during the early postnatal period apparently programs the male liver for GH pulse responsiveness later in life, and this is required for full adult expression of sex-biased genes ( 60 ). Accordingly, cGH infusion in adult male mice, as in the present study, may not be sufficient to abolish the imprinting effects of neonatal GH pulse exposure, and consequently, cGH exposure of adult males may not fully reverse the male chromatin state.…”

Section: Discussionmentioning

confidence: 99%

Feminization of Male Mouse Liver by Persistent Growth Hormone Stimulation: Activation of Sex-Biased Transcriptional Networks and Dynamic Changes in Chromatin States

Lau-Corona

Suvorov

Waxman

2017

Molecular and Cellular Biology

120

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Sex-dependent pituitary growth hormone (GH) secretory profiles—pulsatile in males and persistent in females—regulate the sex-biased, STAT5-dependent expression of hundreds of genes in mouse liver, imparting sex differences in hepatic drug/lipid metabolism and disease risk. Here, we examine transcriptional and epigenetic changes induced by continuous GH infusion (cGH) in male mice, which rapidly feminizes the temporal profile of liver STAT5 activity. cGH repressed 86% of male-biased genes and induced 68% of female-biased genes within 4 days; however, several highly female-specific genes showed weak or no feminization, even after 14 days of cGH treatment. Female-biased genes already in an active chromatin state in male liver generally showed early cGH responses; genes in an inactive chromatin state often responded late. Early cGH-responsive genes included those encoding two GH/STAT5-regulated transcriptional repressors: male-biased BCL6, which was repressed, and female-specific CUX2, which was induced. Male-biased genes activated by STAT5 and/or repressed by CUX2 were enriched for early cGH repression. Female-biased BCL6 targets were enriched for early cGH derepression. Changes in sex-specific chromatin accessibility and histone modifications accompanied these cGH-induced sex-biased gene expression changes. Thus, the temporal, sex-biased gene responses to persistent GH stimulation are dictated by GH/STAT5-regulated transcription factors arranged in a hierarchical network and by the dynamics of changes in sex-biased epigenetic states.

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Section: Discussionmentioning

confidence: 99%

Feminization of Male Mouse Liver by Persistent Growth Hormone Stimulation: Activation of Sex-Biased Transcriptional Networks and Dynamic Changes in Chromatin States

Lau-Corona

Suvorov

Waxman

2017

Molecular and Cellular Biology

120

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“…3). The partial feminization achieved in the latter two mouse models, where GH signaling is disrupted, could be due to early, irreversible postnatal effects of GH, which may imprint (program) liver gene expression patterns [67]. In the case of Sult2a5 and Sult2a6, the high levels of H3K27me3 across the gene body in wild-type male mouse liver were largely abolished in E1/E2-KO male liver (Fig.…”

Section: Discussionmentioning

confidence: 99%

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Lau-Corona

Bae

Hennighausen

et al. 2019

Preprint

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31Background: Sex differences in the incidence and progression of many liver diseases, including liver 32 fibrosis and hepatocellular carcinoma, are associated with sex-biased expression of hundreds of 33 genes in the liver. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary 34 growth hormone secretion, which controls a transcriptional regulatory network operative in the context 35 of sex-biased chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive 36 chromatin mark that is specifically deposited by polycomb repressive complex-2, via its homologous 37 catalytic subunits Ezh1 and Ezh2, at many strongly female-biased genes in male mouse liver, but not 38 at male-biased genes in female liver. Results: We used Ezh1-knockout mice with a hepatocyte-39 specific knockout of Ezh2 to elucidate the sex bias of liver H3K27-trimethylation and its functional role 40 in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant 41 loss of sex-biased gene expression, particularly in male liver, where many female-biased genes 42 increased in expression while male-biased genes showed decreased expression. The associated loss 43 of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also 44 more pronounced in male liver. Many genes linked to liver fibrosis and hepatocellular carcinoma were 45 induced in Ezh1/Ezh2-deficient livers, which may contribute to the increased sensitivity of these mice 46 to hepatotoxin-induced liver pathology. Conclusions: Ezh1/Ezh2-catalyzed H3K27-trimethyation is 47 thus essential for the sex-dependent epigenetic regulation of liver chromatin states controlling 48 phenotypic sex differences in liver metabolism and liver fibrosis, and may be a critical determinant of 49 the sex-bias in liver disease susceptibility. Background 52Liver disease shows marked sex differences. Hepatocellular carcinoma incidence and mortality is 53 three times higher in men than in women [1, 2], and male mice are more susceptible to chemical-54 induced hepatic carcinogenesis [3]. Males are also more susceptible to non-alcoholic fatty liver 55 disease, non-alcoholic steatohepatitis and liver fibrosis than females [4][5][6][7][8]. Underlying these sex-biased Lau-Corona et alPage 5 3/13/19 liver. Hepatic Ezh1/Ezh2 deficiency is also shown to down regulate many male-biased genes, 106presumed as a secondary response to the disruption of female-biased gene expression. Finally, we 107show that many genes associated with liver fibrosis and liver carcinogenesis are differentially 108 responsive to the loss of Ezh1/Ezh2 in male compared to female liver, which may contribute to the 109 observed sex-differences in the incidence and progression of liver cancer. 110 111 Methods 112 Animal tissues. Livers from 7-week-old male and female Ezh1-knockout mice with a hepatocyte-113 specific knockout of Ezh2 (E1/E2-KO mice, also designated Double-knockout (DKO) in the figures 114 and tables) and their age and sex...

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“…It has been described that neonatal and postpubertal sex steroids regulate the hypothalamus on its generation of the gender dimorphism of the pituitary GH secretion seen in adulthood. This could explain the gender dimorphism seen in liver physiology [1,13]. In rodents, gender dimorphism is thought to be controlled by E2 secretion in adult females, whereas it is mediated by T secretion in neonatal and adult males.…”

Section: Sex Steroids Regulate the Pattern Of Pituitary Gh Secretionmentioning

confidence: 99%

“…The liver is as sex steroid-responsive organ [1][2][3][4][5][6][7][8][9][10][11][12][13]. The natural estrogen, 17β-estradiol (E2), and androgens, testosterone (T)/dihydrotestosterone (DHT) have physiological actions, which are not limited to reproductive organs, in both females and males.…”

Section: Introductionmentioning

confidence: 99%

Control of Liver Gene Expression by Sex Steroids and Growth Hormone Interplay

Fernández-Pérez¹,

Mirecki-Garrido²,

Recio³

et al. 2020

Chemistry and Biological Activity of Steroids

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Sex steroids have important physiological actions, which are not limited to reproductive organs, in both females and males. They exert important physiological roles, including the regulation of somatotropic-liver axis, intermediate metabolism, or gender dimorphism. This is in part because the liver is a sex steroid-responsive organ where sex steroid-and growth hormone (GH)-dependent signaling pathways connect to regulate complex gene expression networks. Sex steroids can impact liver gene expression by a direct, through hepatic estrogen receptor (ER)α and androgen receptor (AR), or indirect mechanisms, by modulation of pituitary GH secretion and/or interaction with the GHR-STAT5b signaling pathway. Therefore, deficiency of sex steroid-and GH-dependent signaling pathways might cause a dramatic impact on mammalian liver physiology. In this chapter, we will focus our attention on main concepts and paradigms involved in the role and interplay between sex steroid-and GH-dependent signaling to regulate gene expression networks in the mammalian liver. A better understanding of how sex steroids and interactions with GH-STAT5b signaling pathway influence physiological and pathological states in the liver will contribute to improve clinical management of patients with disorders in body growth, development, and metabolism.Chemistry and Biological Activity of Steroids 2 androgen/AR [6,7,[21][22][23][24][25] or signaling pathways in adults causes a similar metabolic-like syndrome (i.e., fatty liver, adiposity, insulin resistance), a phenotype that might be ameliorated by E2/T or GH replacement. Therefore, the interplay between sex steroids and GH is clinically relevant because of its importance in the regulation of endocrine, metabolic, and gender-differentiated actions on the mammalian liver [33]. A better understanding of this complex sex steroid-GH interplay in physiological and pathological states will contribute to prevent health damage and improve clinical management of patients with growth, developmental, and metabolic disorders. In this review, we will summarize the role of sex steroid-and GH-dependent signaling pathways on liver gene expression. The liver is as sex steroid-responsive organSex steroids can regulate liver gene transcription through direct and indirect mechanisms.

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Growth hormone: a newly identified developmental organizer

Cited by 8 publications

References 54 publications

Feminization of Male Mouse Liver by Persistent Growth Hormone Stimulation: Activation of Sex-Biased Transcriptional Networks and Dynamic Changes in Chromatin States

Feminization of Male Mouse Liver by Persistent Growth Hormone Stimulation: Activation of Sex-Biased Transcriptional Networks and Dynamic Changes in Chromatin States

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Control of Liver Gene Expression by Sex Steroids and Growth Hormone Interplay

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