Distinct STAT5 concentrations uniquely control establishment and differentiation of mammary epithelium during pregnancy
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE37646 | GEO | 2012/05/02
SECONDARY ACCESSION(S): PRJNA162891
REPOSITORIES: GEO
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Project description:To dissect regulatory processes of cell proliferation and differentiation we generated mouse strains carrying any combination of the four Stat5 alleles, thus expressing STAT5 from 0 to 100%. RNA-Seq analyses revealed that different STAT5 levels activate specific genetic programs linked to cell proliferation and differentiation. We refer to wild-type mice and Stat5abfl/fl mice as AABB mice; Stat5abfl/fl;MMTV-Cre (with Stat5ab-deficient mammary epithelial cells) as Null mice; Stat5a-/- mice as BB mice; Stat5b-/- mice as AA mice; Stat5ab+/null mice as AB mice.
2012-05-02 | E-GEOD-37646 | biostudies-arrayexpress
Project description:Cytokines control the expression of common and cell-specific genes through the transcription factor STAT5. In mammary tissue specifically, expression of approximately 570 genes is induced during pregnancy by prolactin through STAT5, which binds to putative regulatory sequences. We have now asked whether mammary-specific induction of these genes can be linked to the presence of additional transcription factors, which would act in concert with STAT5. RNA-seq analysis at parturition identified 370 genes that were under NFIB control. Notably, 75% of these genes, encoding proteins linked to the differentiation of mammary epithelium, were also regulated by STAT5. This study demonstrates that the STAT5-NFIB module is an essential part of genes that define differentiation and function of the mammary gland. Expression profiling by high throughput sequencing in wild-type (WT) and Nfib-null (KO) mammary gland tissues
2012-12-13 | E-GEOD-42878 | biostudies-arrayexpress
Project description:Cytokines control the expression of common and cell-specific genes through the transcription factor STAT5. In mammary tissue specifically, expression of approximately 570 genes is induced during pregnancy by prolactin through STAT5, which binds to putative regulatory sequences. We have now asked whether mammary-specific induction of these genes can be linked to the presence of additional transcription factors, which would act in concert with STAT5. RNA-seq analysis at parturition identified 370 genes that were under NFIB control. Notably, 75% of these genes, encoding proteins linked to the differentiation of mammary epithelium, were also regulated by STAT5. This study demonstrates that the STAT5-NFIB module is an essential part of genes that define differentiation and function of the mammary gland.
2012-12-13 | GSE42878 | GEO
Project description:The transcription factor STAT5 has long been recognized as an important mediator of prolactin induced mammary development during pregnancy. We have used mouse genetics and genome-wide analyses to determine how altering concentrations of STAT5A and STAT5B impacts different target promoters. Examination of genome-wide STAT5A, STAT5B, PolII and H3K4me3 in wild type (AABB) and Stat5a-null (BB) mammary tissues.
2012-09-18 | E-GEOD-40930 | biostudies-arrayexpress
Project description:Transcriptional profiling of mouse osteoclasts comparing control osteoclasts from Stat5 flox mice with osteoclasts from Stat5 cKO mice. Two-condition experiment, Stat5 flox cells vs. Stat5 cKO cells
2013-12-09 | E-GEOD-51283 | biostudies-arrayexpress
Project description:Purpose: Among the diverse cytokines involved in osteoclast differentiation, IL-3 has been shown to inhibit RANKL-induced osteoclastogenesis. However, the mechanism underlying IL-3-mediated inhibition of osteoclast differentiation is not fully understood. In the present study, we demonstrate that IL-3 activation of STAT5 inhibits RANKL-induced osteoclastogenesis through the induction of Id genes. Methods: To investigate the effect of STAT5 on osteoclast differentiation and IL-3-mediated inhibition of osteoclast differentiation, bone marrow derived macrophages isolated from STAT5 wild-type (Stat5fl/fl) or STAT5 cKO (STAT5;MX1-Cre) were differentiated to osteoclast in the presence of M-CSF and RANKL with or without IL-3; and bone marrow derived macrophges from STAT5 wild-type and STAT5 cKO were overexpressed with PMX-FIG (control) or STAT5A1*6 (constitutively active form of STAT5A) and differentiated to osteoclast. To analyze bone phenotype, femurs and tibiae of 16 week-old STAT5 wild-type and STAT5 cKO were subjected to micro CT analysis and histomorphometry, respectively. Results: Overexpression of STAT5 inhibited RANKL-induced osteoclastogenesis. However, RANKL did not regulate either expression or activation of STAT5 during osteoclast differentiation. STAT5 deficiency prevented IL-3-mediated inhibition of osteoclastogenesis, suggesting that STAT5 plays an important role in IL-3-mediated inhibition of osteoclast differentiation. In addition, IL-3-induced STAT5 activation upregulated expression of the Id1 and Id2 genes, which are negative regulators of osteoclastogenesis. Overexpression of ID1 or ID2 in STAT5-deficient cells reversed osteoclast development recovered from IL-3-mediated inhibition. Moreover, micro-computed tomography and histomorphometric analysis revealed that STAT5 conditional knockout mice showed reduced bone mass, with an increased number of osteoclasts. Furthermore, IL-3 inhibited RANKL-induced osteoclast differentiation less effectively in STAT5 conditional knockout mice than in wild-type mice in a RANKL injection model. Conclusion: Taken together, our results suggest that STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis through Id gene expression. Examination of 4 different combination of osteoclast differentiation condition of bone marrow derived macrophages.
2016-08-03 | E-GEOD-76988 | biostudies-arrayexpress
Project description:The transcription factor STAT5 has long been recognized as an important mediator of prolactin induced mammary development during pregnancy. We have used mouse genetics and genome-wide analyses to determine how altering concentrations of STAT5A and STAT5B impacts different target promoters.
2012-09-18 | GSE40930 | GEO
Project description:Cytokine-activated STAT proteins dimerize and bind to high-affinity motifs, and N-terminal domain-mediated oligomerization of dimers allows tetramer formation and binding to low-affinity tandem motifs, but the functions of dimers versus tetramers are unknown. We generated Stat5a and Stat5b double knock-in (DKI) N-domain mutant mice that form dimers but not tetramers, identified cytokine-regulated genes whose expression required STAT5 tetramers, and defined consensus motifs for dimers versus tetramers. Whereas Stat5- deficient mice exhibited perinatal lethality, DKI mice were viable, indicating that STAT5 dimers were sufficient for survival. Nevertheless, STAT5 DKI mice had fewer CD4+CD25+ T cells, NK cells, and CD8+ T cells, with impaired cytokine-induced proliferation and homeostatic proliferation of CD8+ T cells. DKI CD8+ T cell proliferation following viral infection was diminished and DKI Treg cells did not efficiently control colitis. Thus, tetramerization of STAT5 is dispensable for survival but is critical for cytokine responses and normal immune function. T cells were extracted from spleen of wt and STAT5 double knocked in mice, and treated with IL-2. The cells were collected from 0h (without treatment), 2h, 6h and 17h, and chipped on Affy mouse 430 2.0 arrays.
2012-04-24 | E-GEOD-36888 | biostudies-arrayexpress
Project description:Adult haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood and immune cells and must respond to extracellular cues including cytokines. The JAK/STAT pathway is a highly conserved pathway, activated by many cytokines, in which tyrosine-phosphorylated STATs (pSTATs) function as transcription factors. STAT5 is a pivotal downstream mediator of several cytokines known to regulate haematopoiesis but its function in the HSC compartment remains poorly understood. Here we show that STAT5-deficient HSCs exhibited an unusual phenotype - reduced multi-lineage repopulation and self-renewal combined with reduced cell cycle entry and increased differentiation. This reflected not only loss of a canonical pSTAT5 transcriptional program but also loss of distinct functions mediated by tyrosine-unphosphorylated STAT5 (uSTAT5). Consistent with this concept expression of an unphosphorylatable STAT5B mutant constrained HSC differentiation, promoted HSC maintenance and upregulated transcriptional programs associated with quiescence and stemness. Moreover, treatment with a JAK1/2 inhibitor (ruxolitinib) increased the uSTAT5:pSTAT5 ratio, constrained HSC differentiation and proliferation and promoted HSC maintenance, thus phenocopying uSTAT5B overexpression. Our results therefore reveal a previously unrecognized interplay between pSTAT5 and uSTAT5 in the control of HSC function. In addition the demonstration that JAK inhibition promotes HSC maintenance has implications for gene therapy using HSCs and may contribute to the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.
2024-05-29 | GSE223632 | GEO
Project description:Purpose: Among the diverse cytokines involved in osteoclast differentiation, IL-3 has been shown to inhibit RANKL-induced osteoclastogenesis. However, the mechanism underlying IL-3-mediated inhibition of osteoclast differentiation is not fully understood. In the present study, we demonstrate that IL-3 activation of STAT5 inhibits RANKL-induced osteoclastogenesis through the induction of Id genes. Methods: To investigate the effect of STAT5 on osteoclast differentiation and IL-3-mediated inhibition of osteoclast differentiation, bone marrow derived macrophages isolated from STAT5 wild-type (Stat5fl/fl) or STAT5 cKO (STAT5;MX1-Cre) were differentiated to osteoclast in the presence of M-CSF and RANKL with or without IL-3; and bone marrow derived macrophges from STAT5 wild-type and STAT5 cKO were overexpressed with PMX-FIG (control) or STAT5A1*6 (constitutively active form of STAT5A) and differentiated to osteoclast. To analyze bone phenotype, femurs and tibiae of 16 week-old STAT5 wild-type and STAT5 cKO were subjected to micro CT analysis and histomorphometry, respectively. Results: Overexpression of STAT5 inhibited RANKL-induced osteoclastogenesis. However, RANKL did not regulate either expression or activation of STAT5 during osteoclast differentiation. STAT5 deficiency prevented IL-3-mediated inhibition of osteoclastogenesis, suggesting that STAT5 plays an important role in IL-3-mediated inhibition of osteoclast differentiation. In addition, IL-3-induced STAT5 activation upregulated expression of the Id1 and Id2 genes, which are negative regulators of osteoclastogenesis. Overexpression of ID1 or ID2 in STAT5-deficient cells reversed osteoclast development recovered from IL-3-mediated inhibition. Moreover, micro-computed tomography and histomorphometric analysis revealed that STAT5 conditional knockout mice showed reduced bone mass, with an increased number of osteoclasts. Furthermore, IL-3 inhibited RANKL-induced osteoclast differentiation less effectively in STAT5 conditional knockout mice than in wild-type mice in a RANKL injection model. Conclusion: Taken together, our results suggest that STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis through Id gene expression.
2016-08-03 | GSE76988 | GEO