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STAT5 signaling in sexually dimorphic gene expression and growth patterns.

ABSTRACT: The past 10 years have seen enormous advances in our understanding of how cytokine signals are mediated intracellularly. Of particular significance was the discovery of a family of seven Signal Transducer and Activators of Transcription (STAT) proteins. Each of these has now been studied in detail, and appropriate gene-disrupted mouse models are available for all except STAT2 (Leonard and O'Shea 1998). Fetal lethality is observed in Stat3-deficient mice, and various immunodeficiencies characterize mice with disrupted Stat1, Stat4, and Stat6 genes, which is consistent with impaired signaling from the specific cytokines that activate each of these proteins. The recent characterization of Stat5-deficient mice has led to several unanticipated findings that point to diverse biological functions for the two STAT5 forms, STAT5a and STAT5b. These include roles for one or both STAT5 forms in the immune system, hematopoiesis, sexually dimorphic growth, mammary development, hair growth, deposition of adipose tissue, and pregnancy. Here we review the hormone- and cytokine-activated signaling pathways in which STAT5 participates and the extensive evidence, from laboratory animals, that these factors are required for sex-specific aspects of development, including control of body size. Finally, we consider human growth disorders that may involve defects in STAT5-dependent signal transduction.

SUBMITTER: Davey HW

PROVIDER: S-EPMC1288266 | biostudies-literature | 1999 Oct

REPOSITORIES: biostudies-literature

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STAT5 signaling in sexually dimorphic gene expression and growth patterns.

Davey H W HW Wilkins R J RJ Waxman D J DJ

American journal of human genetics 19991001 4

The past 10 years have seen enormous advances in our understanding of how cytokine signals are mediated intracellularly. Of particular significance was the discovery of a family of seven Signal Transducer and Activators of Transcription (STAT) proteins. Each of these has now been studied in detail, and appropriate gene-disrupted mouse models are available for all except STAT2 (Leonard and O'Shea 1998). Fetal lethality is observed in Stat3-deficient mice, and various immunodeficiencies characteri ...[more]

PMID: 10486314

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Project description:BackgroundFetal sex and placental development impact pregnancy outcomes and fetal-maternal health, but the critical timepoint of placenta establishment in first trimester is understudied in human pregnancies.MethodsPregnant subjects were recruited in late first trimester (weeks 10-14) at time of chorionic villus sampling, a prenatal diagnostic test. Leftover placenta tissue was collected and stored until birth outcomes were known, then DNA and RNA were isolated from singleton, normal karyotype pregnancies resulting in live births. DNA methylation was measured with the Illumina Infinium MethylationEPIC BeadChip array (n = 56). Differential methylation analysis compared 25 females versus 31 males using a generalized linear model on 743,461 autosomal probes. Gene expression sex differences were analyzed with RNA-sequencing (n = 74). An integrated analysis was performed using linear regression to correlate gene expression and DNA methylation in 51 overlapping placentas.ResultsMethylation analysis identified 151 differentially methylated probes (DMPs) significant at false discovery rate < 0.05, including 89 (59%) hypermethylated in females. Probe cg17612569 (GABPA, ATP5J) was the most significant CpG site, hypermethylated in males. There were 11 differentially methylated regions affected by fetal sex, with transcription factors ZNF300 and ZNF311 most significantly hypermethylated in males and females, respectively. RNA-sequencing identified 152 genes significantly sexually dimorphic at false discovery rate < 0.05. The 151 DMPs were associated with 18 genes with gene downregulation (P < 0.05) in the direction of hypermethylation, including 2 genes significant at false discovery rate < 0.05 (ZNF300 and CUB and Sushi multiple domains 1, CSMD1). Both genes, as well as Family With Sequence Similarity 228 Member A (FAM228A), showed significant correlation between DNA methylation and sexually dimorphic gene expression, though FAM228A DNA methylation was less sexually dimorphic. Comparison with other sex differences studies found that cg17612569 is male-hypermethylated across gestation in placenta and in human blood up to adulthood.ConclusionsOverall, sex dimorphic differential methylation with associated differential gene expression in the first trimester placenta is small, but there remain significant genes that may be regulated through methylation leading to differences in the first trimester placenta.

Project description:BackgroundCurrent methods fail to accurately predict women at greatest risk of developing fetal growth restriction (FGR) or related adverse outcomes, including stillbirth. Sexual dimorphism in these adverse pregnancy outcomes is well documented as are sex-specific differences in gene and protein expression in the placenta. Circulating maternal serum microRNAs (miRNAs) offer potential as biomarkers that may also be informative of underlying pathology. We hypothesised that FGR would be associated with an altered miRNA profile and would differ depending on fetal sex.MethodsmiRNA expression profiles were assessed in maternal serum (> 36 weeks' gestation) from women delivering a severely FGR infant (defined as an individualised birthweight centile (IBC) < 3rd) and matched control participants (AGA; IBC = 20-80th), using miRNA arrays. qPCR was performed using specific miRNA primers in an expanded cohort of patients with IBC < 5th (n = 15 males, n = 16 females/group). Maternal serum human placental lactogen (hPL) was used as a proxy to determine if serum miRNAs were related to placental dysfunction. In silico analyses were performed to predict the potential functions of altered miRNAs.ResultsInitial analyses revealed 11 miRNAs were altered in maternal serum from FGR pregnancies. In silico analyses revealed all 11 altered miRNAs were located in a network of genes that regulate placental function. Subsequent analysis demonstrated four miRNAs showed sexually dimorphic patterns. miR-28-5p was reduced in FGR pregnancies (p < 0.01) only when there was a female offspring and miR-301a-3p was only reduced in FGR pregnancies with a male fetus (p < 0.05). miR-454-3p was decreased in FGR pregnancies (p < 0.05) regardless of fetal sex but was only positively correlated to hPL when the fetus was female. Conversely, miR-29c-3p was correlated to maternal hPL only when the fetus was male. Target genes for sexually dimorphic miRNAs reveal potential functional roles in the placenta including angiogenesis, placental growth, nutrient transport and apoptosis.ConclusionsThese studies have identified sexually dimorphic patterns for miRNAs in maternal serum in FGR. These miRNAs may have potential as non-invasive biomarkers for FGR and associated placental dysfunction. Further studies to determine if these miRNAs have potential functional roles in the placenta may provide greater understanding of the pathogenesis of placental dysfunction and the differing susceptibility of male and female fetuses to adverse in utero conditions.

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STAT5 signaling in sexually dimorphic gene expression and growth patterns.

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STAT5 signaling in sexually dimorphic gene expression and growth patterns.

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