scholarly journals Role of STAT5a in regulation of sex-specific gene expression in female but not male mouse liver revealed by microarray analysis

2007 ◽  
Vol 31 (1) ◽  
pp. 63-74 ◽  
Author(s):  
Karl H. Clodfelter ◽  
Gregory D. Miles ◽  
Valerie Wauthier ◽  
Minita G. Holloway ◽  
Xiaohua Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Intracellular Signaling ◽  
Specific Gene ◽  
Sexually Dimorphic ◽  
Wild Type ◽  
Specific Gene Expression ◽  
Sex Specificity ◽  
Liver Gene ◽  
Plasma Gh

Sexual dimorphism in mammalian liver impacts genes affecting hepatic physiology, including inflammatory responses, diseased states, and the metabolism of steroids and foreign compounds. Liver sex specificity is dictated by sex differences in pituitary growth hormone (GH) secretion, with the transcription factor signal transducer and activator of transcription (STAT)5b required for intracellular signaling initiated by the pulsatile male plasma GH profile. STAT5a, a minor liver STAT5 form >90% identical to STAT5b, also responds to sexually dimorphic plasma GH stimulation but is unable to compensate for the loss of STAT5b and the associated loss of sex-specific liver gene expression. A large-scale gene expression study was conducted using 23,574-feature oligonucleotide microarrays and livers of male and female mice, both wild-type and Stat5a-inactivated mice, to elucidate any dependence of liver gene expression on STAT5a. Significant sex differences in expression were found for 2,482 mouse genes, 1,045 showing higher expression in males and 1,437 showing higher expression in females. In contrast to the widespread effects of the loss of STAT5b, STAT5a deficiency had a limited but well-defined impact on liver sex specificity, with 219 of 1,437 female-predominant genes (15%) specifically decreased in expression in STAT5a-deficient female liver. Analysis of liver RNAs from wild-type mice representing three mixed or outbred strains identified 1,028 sexually dimorphic genes across the strains, including 393 female-predominant genes, of which 89 (23%) required STAT5a for normal expression in female liver. These findings highlight the importance of STAT5a for regulation of sex-specific gene expression specifically in female liver, in striking contrast to STAT5b, whose major effects are restricted to male liver.

scholarly journals Sex-specific gene expression in the BXD mouse liver

2010 ◽  
Vol 42 (3) ◽  
pp. 456-468 ◽  
Author(s):  
Daniel M. Gatti ◽  
Ni Zhao ◽  
Elissa J. Chesler ◽  
Blair U. Bradford ◽  
Andrey A. Shabalin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Genetic Variation ◽  
Inbred Strains ◽  
Major Effect ◽  
Specific Gene ◽  
Sexually Dimorphic ◽  
Expression Data ◽  
Data Set ◽  
Liver Gene

Differences in clinical phenotypes between the sexes are well documented and have their roots in differential gene expression. While sex has a major effect on gene expression, transcription is also influenced by complex interactions between individual genetic variation and environmental stimuli. In this study, we sought to understand how genetic variation affects sex-related differences in liver gene expression by performing genetic mapping of genomewide liver mRNA expression data in a genetically defined population of naive male and female mice from C57BL/6J, DBA/2J, B6D2F1, and 37 C57BL/6J × DBA/2J (BXD) recombinant inbred strains. As expected, we found that many genes important to xenobiotic metabolism and other important pathways exhibit sexually dimorphic expression. We also performed gene expression quantitative trait locus mapping in this panel and report that the most significant loci that appear to regulate a larger number of genes than expected by chance are largely sex independent. Importantly, we found that the degree of correlation within gene expression networks differs substantially between the sexes. Finally, we compare our results to a recently released human liver gene expression data set and report on important similarities in sexually dimorphic liver gene expression between mouse and human. This study enhances our understanding of sex differences at the genome level and between species, as well as increasing our knowledge of the molecular underpinnings of sex differences in responses to xenobiotics.

scholarly journals 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

2006 ◽  
Vol 20 (6) ◽  
pp. 1333-1351 ◽  
Author(s):  
Karl H. Clodfelter ◽  
Minita G. Holloway ◽  
Paul Hodor ◽  
Soo-Hee Park ◽  
William J. Ray ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Large Scale ◽  
Dependent Manner ◽  
Signal Transducer ◽  
Genotype Combination ◽  
Hepatic Expression ◽  
Gh Secretion ◽  
Liver Gene ◽  
Plasma Gh

Abstract Sexual dimorphism in mammalian liver contributes to sex differences in physiology, homeostasis, and steroid and foreign compound metabolism. Many sex-dependent liver genes are regulated by sex differences in pituitary GH secretion, with the transcription factor, signal transducer and activator of transcription (STAT5b), proposed to mediate signaling by the pulsatile, male plasma GH profile. Presently, a large-scale gene expression study was conducted using male and female mice, wild type and Stat5b inactivated, to characterize sex differences in liver gene expression and their dependence on STAT5b. The relative abundance of individual liver RNAs was determined for each sex-genotype combination by competitive hybridization to 23,574-feature oligonucleotide microarrays. Significant sex differences in hepatic expression were seen for 1603 mouse genes. Of 850 genes showing higher expression in males, 767 (90%) were down-regulated in STAT5b-deficient males. Moreover, of 753 genes showing female-predominant expression, 461 (61%) were up-regulated in STAT5b-deficient males. In contrast, approximately 90% of the sex-dependent genes were unaffected by STAT5b deficiency in females. Thus: 1) STAT5b is essential for sex-dependent liver gene expression, a characteristic of approximately 1600 mouse genes (4% of the genome); 2) male-predominant liver gene expression requires STAT5b, or STAT5b-dependent factors, which act in a positive manner; and 3) many female-predominant liver genes are repressed in males in a STAT5b-dependent manner. Several of the STAT5b-dependent male genes encode transcriptional repressors; these may include direct STAT5b targets that repress female-predominant genes in male liver. Several female-predominant repressors are elevated in STAT5b-deficient males; these may contribute to the major loss of male gene expression seen in the absence of STAT5b.

Increased Thrombosis in Male Versus Female Mice Is Mediated by Pulsatile Growth Hormone Secretion Possibly through Inhibition of TFPI Expression in the Vasculature.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 266-266
Author(s):  
Joshua H. Wong ◽  
Robert E. Levy ◽  
Jonathan Dukes ◽  
Sara A. Mason ◽  
Brandon Sos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Hormone ◽  
Sex Differences ◽  
Median Survival ◽  
Growth Hormone Secretion ◽  
Gene Copy ◽  
Sexually Dimorphic ◽  
Liver Protein ◽  
Gh Secretion ◽  
Liver Gene

Abstract Clinical reports suggest significant sex differences in risk for thrombosis-related diseases such as myocardial infarction, stroke, and venous thromboembolism. However, little is known about mechanism for such differences. There is a well-described sexual dimorphism in liver protein synthesis that is growth hormone (GH) dependent. GH secretion from the pituitary is itself highly sexually dimorphic with males (M) secreting in a pulsatile (P) and females (F) a continuous (C) fashion. These patterns induce M- and F-specific signatures of liver gene expression. In the past, we and others have observed significant sex differences in murine thrombosis models. Given that most coagulation proteases and inhibitors are synthesized or modified in the liver, we aimed to test whether sex-specific GH secretion patterns contribute to the observed sex differences in thrombosis. We measured whole blood clotting times (WCT), thrombosis susceptibility in the thromboplastin-mediated pulmonary embolism (PE) model, and hemostasis in the tail bleeding time (BT) model in M and F control (WT) and GH-deficient “little” (LIT) mice. We observed that WT Fs had longer WCTs (mean time 61.38 vs. 56.72 sec) and were significantly protected in the PE model (median survival 232.5 vs 165 sec) as compared to M. There were no differences in the BT model across all experiments. Interestingly, F and M LIT animals both had significantly prolonged WCTs (67.56 and 67.30 sec, respectively) and were substantially protected in the PE model (median survival 900 and 1200 sec) as compared to WT. Next, LIT animals were injected twice daily with GH to simulate the P pattern of GH secretion (LIT+). This resulted in a significant shortening of the F and M WCTs back to WT M levels (53.16 and 50.97 sec). A group of F WT animals were also injected with M pattern GH (WT+). This too resulted in significant shortening of the F WCTs (54.10 sec). To explore for possible mechanisms underlying these differences, we measured activity of coagulation factors II, V, VII, VIII, IX, X, and XI. The average of all factor activity levels was significantly higher in WT M vs F (100 vs. 81.99%), significantly lower and in both M and F LIT (60.85 and 57.97%), and increased to WT M levels in M and F LIT+ animals (106.6 and 99%). To determine whether these changes were mediated by changes in liver gene expression, we measured a panel of 30 coagulation protease and inhibitor genes in liver and vascular tissue by Taqman®. Surprisingly, we found no significant differences in coagulation factor expression, but found that expression of TFPI was significantly increased in F vs M WT vasculature (9431 vs. 7678 gene copy number (GCN)). Expression was increased in M and F LIT animals (10350 and 11710 GCN) and fell to below WT levels in M and F LIT+ animals (4534 and 4194 GCN). These results indicate that sex differences in thrombosis in mice are at least in part mediated by sex differences in GH secretion with F mice relatively protected as compared to M. M and F GH-deficient LIT mice are similarly protected as compared to WT M. Repletion of GH in a P pattern reverts M and F LIT and F WT mice to WT M levels. Finally, P GH secretion may promote increased thrombosis through inhibition of TFPI in the vasculature. This represents a novel mechanism underlying these sex-differences in thrombosis mediated by sexually dimorphic GH secretion and its effect on regulation of TFPI in the vasculature.

scholarly journals The effect of neurogenin3 deficiency on pancreatic gene expression in embryonic mice

2006 ◽  
Vol 37 (2) ◽  
pp. 301-316 ◽  
Author(s):  
Andreas Petri ◽  
Jonas Ahnfelt-Rønne ◽  
Klaus Stensgaard Frederiksen ◽  
David George Edwards ◽  
Dennis Madsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microarray Analysis ◽  
Molecular Mechanisms ◽  
Homeobox Gene ◽  
Specific Gene ◽  
Wild Type ◽  
Specific Gene Expression ◽  
And Function ◽  
Deficient Mice

To understand the molecular mechanisms regulating pancreatic endocrine development and function, pancreatic gene expression was compared between Ngn3-deficient mice and littermate controls on embryonic days 13 and 15. Microarray analysis identified 504 genes with significant differences in expression. Fifty-two of these showed at least twofold reduction in Ngn3 knockouts compared to controls. Many of them were previously described to be involved in endocrine development and function. Among the genes not previously characterized were Rhomboid veinlet-like 4, genes involved in tetrahydrobiopterin biosynthesis and the Iroquois-type homeobox gene Irx1, the latter was selected for further investigation. In situ hybridisation demonstrated that two Iroquois genes, Irx1 and Irx2, were expressed in pancreatic endoderm of wild-type, but not Ngn3 mutant embryos. Furthermore, ectopic Ngn3 induced prominent Irx2 expression in chicken endoderm. Co-labelling established that Irx1 and Irx2 mRNA is located to glucagon-, but not insulin- or somatostatin-producing cells in mice and chicken. These data suggest that Irx1 and Irx2 serve an evolutionary conserved role in the regulation of α-cell-specific gene expression.

scholarly journals GATA-2 and GATA-3 regulate trophoblast-specific gene expression in vivo

Development ◽  
1997 ◽  
Vol 124 (4) ◽  
pp. 907-914 ◽  
Author(s):  
G.T. Ma ◽  
M.E. Roth ◽  
J.C. Groskopf ◽  
F.Y. Tsai ◽  
S.H. Orkin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Giant Cells ◽  
Placental Lactogen ◽  
Specific Gene ◽  
Wild Type ◽  
Specific Gene Expression ◽  
Decidual Tissue ◽  
Trophoblast Giant Cells ◽  
I Gene

We previously demonstrated that the zinc finger transcription factors GATA-2 and GATA-3 are expressed in trophoblast giant cells and that they regulate transcription from the mouse placental lactogen I gene promoter in a transfected trophoblast cell line. We present evidence here that both of these factors regulate transcription of the placental lactogen I gene, as well as the related proliferin gene, in trophoblast giant cells in vivo. Placentas lacking GATA-3 accumulate placental lactogen I and proliferin mRNAs to a level 50% below that reached in the wild-type placenta. Mutation of the GATA-2 gene had a similar effect on placental lactogen I expression, but led to a markedly greater reduction (5- to 6-fold) in proliferin gene expression. Placentas lacking GATA-2 secrete significantly less angiogenic activity than wild-type placentas as measured in an endothelial cell migration assay, consistent with a reduction in expression of the angiogenic hormone proliferin. Furthermore, within the same uterus the decidual tissue adjacent to mutant placentas displays markedly reduced neovascularization compared to the decidual tissue next to wild-type placentas. These results indicate that GATA-2 and GATA-3 are important in vivo regulators of trophoblast-specific gene expression and placental function, and reveal a difference in the effect of these two factors in regulating the synthesis of related placental hormones.

High Rate of FLT3 Mutations In Adult ETP-ALL.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1031-1031 ◽  
Author(s):  
Martin Neumann ◽  
Ebru Coskun ◽  
Ouidad Benlasfer ◽  
Sandra Heesch ◽  
Stefan Schwartz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Expression Pattern ◽  
Mirna Expression ◽  
Lymphoblastic Leukemia ◽  
Specific Gene ◽  
Wild Type ◽  
Specific Gene Expression ◽  
Flt3 Mutation ◽  
Flt3 Mutations

Abstract Abstract 1031 Introduction: Mutations of FLT3 are recognized as important prognostic factor in acute myeloid leukemia (AML) with an impact on new therapeutic strategies. However, FLT3 mutations are rarely (1-3%) found in acute T-lymphoblastic leukemia (T-ALL). Recently, a new T-ALL subgroup defined by a specific gene expression profile and a characteristic immunophenotype (CD1a-, CD8-, CD5weak with expression of stem cell or myeloid markers) and with poor outcome has been described in pediatric T-ALL patients. This subgroup likely originates from early thymic progenitors (ETP) and has therefore been termed ETP-ALL. To unravel the molecular alterations of this distinct subgroup with myeloid characteristics, we studied adult ETP-ALL patients for FLT3 mutations. Moreover, we analyzed miRNA expression to explore their potential involvement in the specific gene expression signature observed in ETP-ALL. Patients and methods: We screened 1241 peripheral blood and bone marrow samples of T-ALL patients that were sent to the central diagnostic reference laboratory of the German Acute Lymphoblastic Leukemia Multicenter Study Group (GMALL). Of the immunophenotypically identified ETP-ALL patients (n=142), sufficient material was available in 70 cases. FLT3 mutations (ITD and TKD) were assessed using the FLT3 mutation assay (InVivoScribe Technologies, San Diego, USA). Expression of miRNAs was first screened by TaqMan low density arrays including 667 miRNAs in ETP-ALL (n=8) and compared to non-ETP T-ALL (n=6). Subsequently, expression of miR-221 and miR-222 was examined by real-time PCR in all 70 ETP-ALL. Results: In our cohort of 1241 T-ALL, 142 (11.4 %) patients showed an immunophenotype of an ETP-ALL, which is in the range of reported frequencies in pediatric patients. Among the 70 ETP-ALL samples analyzed, we identified 9 patients with a FLT3 D835 mutation and 15 patients with a FLT3 ITD. In total, 34 % (24 of the 70) patients carried a FLT3 mutation, which represents approximately 4 % of all T-ALL patients. In contrast, only one patient was identified with a FLT3 mutation within an arbitrarily selected control group of 107 T-ALL patients with a non-ETP immunophenotype. Interestingly, ETP-ALL with FLT3 mutations showed a distinct immunophentype compared to ETP-ALL with a wild type FLT3: ETP-ALL with FLT3 mutations had a higher rate of positivity for CD2 (88% vs. 30%, P<0.001), CD117 (83% vs. 28%, P<0.001), and CD13 (100 % vs. 37%, P<0.001). On the other hand, ETP-ALL with wild type FLT3 were characterized by a more frequent positivity of CD5 (54% vs. 4%, P<0.001) and CD33 (54% vs. 4%, P<0.001). Based on these findings a specific immunophenotype may be linked to FLT3 mutated ETP-ALL: in 73% (21/29) of patients with CD2/CD13 positivity a FLT3 mutation was present, compared to only 7% (3/41) of the remaining patients with ETP-ALL. In addition, we generated miRNA expression profiles in ETP-ALL and identified 7 miRNAs that were differentially expressed compared to non-ETP T-ALL. Among these miR-221 and miR-222, which were significantly overexpressed in ETP-ALL, are targeting genes characterizing the ETP-ALL phenotype (e.g. ETS1, KIT). Examination of miR-221 and miR-222 in 70 ETP-ALL revealed their particular overexpression in FLT3 mutated samples (miR-221 2.45-fold, P=0.012; miR-222: 2.05-fold, P=0.008) compared to ETP-ALL with wild type FLT3. Conclusion: We identified a yet unreported high frequency of FLT3 mutations in T-ALL, which are nearly exclusively found within the subgroup of ETP-ALL. In this group the rate is comparable high to the rate of FLT3 mutations in AML. Therefore, on the basis of established flow cytometry analysis we identified T-ALL patients that should be now prospectively and routinely screened for FLT3 mutations. Moreover, the distinct miRNA expression pattern may impact on the specific gene expression pattern of ETP-ALL. Thus, patients of this molecular distinct ETP-ALL entity may benefit from tyrosine kinase inhibitors in relapse situations or with presence of minimal residual disease as a bridging therapy to allogeneic stem cell transplantation. Disclosures: Baldus: Novartis: Research Funding.

scholarly journals Estrogen Receptor-α Suppresses Liver Carcinogenesis and Establishes Sex-Specific Gene Expression

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2355
Author(s):  
Mara H. O’Brien ◽  
Henry C. Pitot ◽  
Sang-Hyuk Chung ◽  
Paul F. Lambert ◽  
Norman R. Drinkwater ◽  
...  
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor ◽  
Expression Patterns ◽  
Estrogen Receptor Α ◽  
Specific Gene ◽  
Wild Type ◽  
Liver Carcinogenesis ◽  
Specific Expression ◽  
Liver Gene ◽  
Female Specific

Estrogen protects females from hepatocellular carcinoma (HCC). To determine whether this protection is mediated by classic estrogen receptors, we tested HCC susceptibility in estrogen receptor-deficient mice. In contrast to a previous study, we found that diethylnitrosamine induces hepatocarcinogenesis to a significantly greater extent when females lack Esr1, which encodes Estrogen Receptor-α. Relative to wild-type littermates, Esr1 knockout females developed 9-fold more tumors. Deficiency of Esr2, which encodes Estrogen Receptor-β, did not affect liver carcinogenesis in females. Using microarrays and QPCR to examine estrogen receptor effects on hepatic gene expression patterns, we found that germline Esr1 deficiency resulted in the masculinization of gene expression in the female liver. Six of the most dysregulated genes have previously been implicated in HCC. In contrast, Esr1 deletion specifically in hepatocytes of Esr1 conditional null female mice (in which Cre was expressed from the albumin promoter) resulted in the maintenance of female-specific liver gene expression. Wild-type adult females lacking ovarian estrogen due to ovariectomy, which is known to make females susceptible to HCC, also maintained female-specific expression in the liver of females. These studies indicate that Esr1 mediates liver cancer risk, and its control of sex-specific liver gene expression involves cells other than hepatocytes.

scholarly journals STAT5b Is Required for GH-Induced Liver Igf-I Gene Expression

Endocrinology ◽  
2001 ◽  
Vol 142 (9) ◽  
pp. 3836-3841 ◽  
Author(s):  
Helen W. Davey ◽  
Tao Xie ◽  
Michael J. McLachlan ◽  
Richard J. Wilkins ◽  
David J. Waxman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intracellular Signaling ◽  
Normal Liver ◽  
Receptor Expression ◽  
Janus Kinase ◽  
Sexually Dimorphic ◽  
Wild Type ◽  
Gh Secretion ◽  
Igf I ◽  
I Gene

Abstract Although the increased expression of Igf-I in liver in response to GH is well characterized, the intracellular signaling pathways that mediate this effect have not been identified. Intracellular signaling molecules belonging to the Janus kinase-signal transducer and activator of transcription 5b (JAK2-STAT5b) pathway are activated by GH and have previously been shown to be required for sexually dimorphic body growth and the expression of liver cytochrome P450 proteins known to be regulated by the gender-specific temporal patterns of pituitary GH secretion. Here, we evaluate the role of STAT5b in GH activation of Igf-I by monitoring the induction of Igf-I mRNA in livers of wild-type and Stat5b−/−mice stimulated with exogenous pulses of GH. GH induced the expression of liver Igf-I mRNA in hypophysectomized male wild-type, but not in hypophysectomized male Stat5b−/− mice, although theStat5b−/− mice exhibit both normal liver GH receptor expression and strong GH induction of Cytokine-inducible SH2 protein (Cis), which is believed to contribute to the down-regulation of GH-induced liver STAT5b signaling. Thus, STAT5b plays an important and specific role in liver Igf-I gene expression.

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