Intrinsic Sex Differences in the Early Growth Hormone Responsiveness of Sex-Specific Genes in Mouse Liver

Wauthier, Valérie; Sugathan, Aarathi; Meyer, Rosana D.; Dombkowski, Alan A.; Waxman, David J.

doi:10.1210/jcem.95.2.9993

Cited by 7 publications

(13 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To validate our microarray results, we performed qPCR for a set of DE genes and sex-specific genes that had previously been shown to be regulated by growth hormone (GH) [20][21][22][23]. The microarray values were very similar to the qPCR values for most of the genes examined ( Supplementary Table S3).…”

Section: Most Androgen-and Stat5b-sensitive Hepatic Genes Are Also Grmentioning

confidence: 69%

See 1 more Smart Citation

Genetic background determines if Stat5b suppresses or enhances murine hepatocarcinogenesis

Oberley

Bilger

Drinkwater

2014

Molecular Carcinogenesis

View full text Add to dashboard Cite

Murine hepatocarcinogenesis requires growth hormone (GH). To determine if the GH-responsive transcription factor STAT5b (signal transducer and activator of transcription 5b) is also required, we compared the hepatic gene expression profiles of global Stat5b null mice to cancer-resistant mice mutant in the GH pathway -- GH-deficient little and androgen receptor-null Tfm males. We found a high degree of overlap among Tfm, little, and Stat5b null males. The liver cancer susceptibility of global Stat5b null mice was assessed on three distinct genetic backgrounds: BALB/cJ (BALB), C57BL/6J (B6), and C3H/HeJ (C3H). The effect of Stat5b on hepatocarcinogenesis depended on the genetic background. B6 Stat5b null congenic males and females developed 2.4 times as many tumors as wild-type (WT) controls (P < 0.002) and the tumors were larger (P < 0.003). In BALB/c congenics, loss of STAT5b had no effect on either sex. C3H Stat5b null congenic males and females were resistant to liver cancer, developing 2.7- and 6-fold fewer tumors, respectively (P < 0.02, 0.003). These results provide the first example of a single gene behaving as both oncogene and tumor suppressor in a given tissue, depending only on the endogenous modifier alleles carried by different genetic backgrounds.

show abstract

Section: Most Androgen-and Stat5b-sensitive Hepatic Genes Are Also Grmentioning

confidence: 69%

“…Half of the mouse orthologs to these human sexbiased genes also show sex-biased expression in the mouse liver. Of the sex-biased genes common to human and mouse or rat, 75% were shown to be primarily regulated by pituitary GH based on their response to hypophysectomy [22,23].…”

Section: Introductionmentioning

confidence: 99%

Genetic background determines if Stat5b suppresses or enhances murine hepatocarcinogenesis

Oberley

Bilger

Drinkwater

2014

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…Sex differences in mouse and human liver are linked to the sex-specific pattern of growth hormone secretion by the pituitary gland [69][70][71]. While we have demonstrated the presence of proximal and distal sex-biased looping in mouse liver, it is not clear how dynamic these loops are in response to factors that dysregulate sexbiased gene expression following alterations in hormone patterns [72] or xenobiotic exposure [60].…”

Section: Matthews and Waxman -Pagementioning

confidence: 64%

Impact of 3-dimensional genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

Matthews

Waxman

2019

Preprint

Self Cite

View full text Add to dashboard Cite

More than 1,000 genes are differentially expressed between male and female mouse liver. However, ~90% of 4,000 sex-differential open chromatin regions harboring regulatory elements implicated in liver sex bias are distal enhancers. To elucidate the role of 3D nuclear organization and address the challenge of linking distal regulatory regions to sex-biased gene targets, we performed ChIP-seq for CTCF and cohesin, known mediators of 3D nuclear organization, and identified ~1,000 binding sites showing significant differential occupancy by these factors in male and female mouse liver. Distal genomic regions showing sex-differential CTCF and/or cohesin binding were evaluated as potential factors in sex-dependent looping controlling sex-biased proximal effects on gene expression. Results were integrated with a study of cohesin depletion in mouse liver to evaluate the impact of cohesin loss on the expression of putative gene targets. Further, circularized chromosome conformation capture with sequencing (4C-seq) was used to discover striking sex-differences in 3D looping, linking distal sex-biased enhancers to proximal sex-biased gene expression for both male-biased (C9, Nudt7, Nox4) and female-biased genes (A1bg, Sult3a2). Our findings also illustrate the importance of a nested intra-TAD loop for insulation of sex-specific enhancer-promoter contacts for Nox4. These studies reveal how chromatin interactions and 3-dimensional genome organization guided both directly and indirectly by CTCF and cohesin looping contribute to liver sex bias. Matthews and Waxman -page 2Here we took a multi-pronged approach to characterize the role of architectural proteins and 3D genome organization in the maintenance of mouse liver sex differences. First, we performed ChIP-seq for CTCF and cohesin using chromatin from male and female mouse livers and show that the majority of sex-biased binding of these factors occurs at distal intergenic sites. Only a minority of these binding sites are cis to sex-biased genes, which may cis-proximal (within 20 kb) or more cis-distal (> 20 kb, but within the same TAD) to a sex biased gene. Specific examples of cis proximal and distal CTCF/cohesin binding are shown for male-biased genes (proximal: Cml5, Nat8; distal, C8a, C8b) and female-biased genes (proximal: Fam84b; distal: Slc22a29). Using a publicly available cohesin depletion dataset for male liver [21], we find that distally-regulated malebiased genes are considerably more sensitive to cohesin loss than those with proximal sex bias. To directly measure differences in chromatin interactions, we use 4C-seq for six viewpoints at or nearby five genes showing liver sex bias in expression, ranging from 2-fold to 700-fold (female-biased: A1bg and Sult3a1; malebiased: C9, Nudt7, and Nox4). Finally, we show the importance of a nested intra-TAD loop for insulation of enhancer-promoter contacts for Nox4. Overall, we describe how 3-dimensional genome organization contributes to liver sex bias in both direct and indirect ways. RESULTS Global differences in CTCF/Coh...

show abstract

“…To test the premise that a change in GH pulse patterning in goat −/− mice may contribute to a similar shift in GH‐dependent liver function, we assessed liver mRNA expression of a subset of genes that are sexually dimorphic and predominantly regulated by GH/Stat5b signalling. Gene targets were isolated to the P450 gene family [including Cyp2d9 , Cyp3a44 , Cyp4a12b , Cyp7b1 ] and Mup1 , a member of the major urinary gene family . Gene expression was comparable between genotypes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To determine liver mRNA expression of GH/Stat5 dependent sexually dimorphic liver genes [ Mup1 , Cyp2d9 , Cyp3a44 , Cyp4a12 and Cyp7b1 – ], the left lateral lobe of the liver was lysed and homogenised using QIAzol lysis reagent (1023537; Qiagen, Hilden, Germany). Total RNA was isolated by RNeasy Microarray Tissue mini kit (73304; Qiagen), in accordance with the manufacturer's instructions, and cDNA was synthesised using the RT 2 HT First Strand synthesis kit (330411; Qiagen).…”

Section: Methodsmentioning

confidence: 99%

Effect of Deletion of Ghrelin‐O‐Acyltransferase on the Pulsatile Release of Growth Hormone in Mice

Xie

Ngo

Veldhuis

et al. 2015

J Neuroendocrinology

View full text Add to dashboard Cite

Ghrelin, a gut hormone originating from the post-translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin-O-acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated ghrelin. Complete loss of preproghrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl-ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat(-/-) mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat(-/-) mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat(-/-) mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat(-/-) mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of altered GH secretory patterning remains unclear, we propose that this may contribute to sustained IGF-1 release and growth in goat(-/-) mice.

show abstract

Intrinsic Sex Differences in the Early Growth Hormone Responsiveness of Sex-Specific Genes in Mouse Liver

Cited by 7 publications

References 0 publications

Genetic background determines if Stat5b suppresses or enhances murine hepatocarcinogenesis

Genetic background determines if Stat5b suppresses or enhances murine hepatocarcinogenesis

Impact of 3-dimensional genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

Effect of Deletion of Ghrelin‐O‐Acyltransferase on the Pulsatile Release of Growth Hormone in Mice

Contact Info

Product

Resources

About