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STAT5 paralog dose governs T cell effector and regulatory function

ABSTRACT: The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remains controversial. We addressed this longstanding question in primary CD4+ 'helper' T cells, the principal orchestrators of adaptive immunity. Using a combination of genetic and genomic approaches, we demonstrate that, although both influence regulatory (Treg) and effector T cell responses, and control many of the same genes, they are not functionally equivalent and, in fact, only the latter is required for immunological tolerance. Differences in genomic distribution and transcriptomic output support the conclusion that STAT5B is dominant and, surprisingly, point towards relative abundance (i.e. paralog dose), rather than unique functional capabilities, as the principal distinguishing feature. Collectively, our data provide a unifying model for the discrete and redundant activities of STAT5A and STAT5B, establishing that asymmetrical expression underlies paralog specificity (or dominance) in the face of widespread structural homology.

ORGANISM(S): Mus musculus

PROVIDER: GSE77656 | GEO | 2016/03/28

SECONDARY ACCESSION(S): PRJNA311157

REPOSITORIES: GEO

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STAT5 paralog dose governs T cell effector and regulatory function

Project description:The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remains controversial. We addressed this longstanding question in primary CD4+ 'helper' T cells, the principal orchestrators of adaptive immunity. Using a combination of genetic and genomic approaches, we demonstrate that, although both influence regulatory (Treg) and effector T cell responses, and control many of the same genes, they are not functionally equivalent and, in fact, only the latter is required for immunological tolerance. Differences in genomic distribution and transcriptomic output support the conclusion that STAT5B is dominant and, surprisingly, point towards relative abundance (i.e. paralog dose), rather than unique functional capabilities, as the principal distinguishing feature. Collectively, our data provide a unifying model for the discrete and redundant activities of STAT5A and STAT5B, establishing that asymmetrical expression underlies paralog specificity (or dominance) in the face of widespread structural homology. This dataset includes 55 individual samples of transcriptome or STAT5 distibution data from cytokine treated CD4+T cells. Each culture condition includes at least 2 biological replicates per genotype.

2016-03-28 | E-GEOD-77656 | biostudies-arrayexpress

RNA-seq data from wildtype, STAT5A-knockout and STAT5B-knockout BCR/ABLp185+ transformed mouse bone marrow cell lines

Project description:RNA-Seq of immortalized Stat5a-/-, Stat5b-/-, and wildtype BCR/ABLp185+ cell lines was used to identify STAT5A and STAT5B specific target genes.

2019-10-01 | GSE121246 | GEO

Prolactin-inducible Stat5a-mediated and Stat5b-mediated gene profiles

Project description:Stat5a and Stat5b proteins are highly homologous with greater than 90% amino acid identity and share binding to the palindromic Stat5 consensus sequence, TTCNNNGAA, but individual roles of each transcription factor in breast cancer have not been thoroughly evaluated. To determine the degree of similarity between transcripts modulated by Stat5a and Stat5b proteins in human breast cancer, we utilized genome-wide transcript profiling to identify genes regulated specifically by Stat5a or Stat5b in response to prolactin. Stat5a or Stat5b was transiently overexpressed using adenoviral gene delivery in MCF7 breast cancer cells followed 16 hr serum starvation and a brief 4 hr exposure to 10nM human prolactin to identify immediate-early transcripts modulated by each transcription factor. Basal activation of Stat5a or Stat5b was not present in cells not stimulated with prolactin. mRNA from each condition was harvested and validated using the Agilent bioanalyzer. cDNA was generated and genome-wide transcript profiling was performed in triplicate using the Affymetrix HuGene 1.0 ST array.

2012-08-29 | E-GEOD-37781 | biostudies-arrayexpress

Prolactin-inducible Stat5a-mediated and Stat5b-mediated gene profiles

2012-08-29 | GSE37781 | GEO

Genetic modification of STAT5 levels reveals dose-dependent and isoform-specific requirement for cell lineage progression and differentiation.

Project description:Two highly conserved transcription factors STAT5A and STAT5B play an identical role in the intracellular signaling pathway upon cytokine stimulation, while gene deletion experiments have revealed separable and overlapping functions of STAT5. This questions whether the phenotypic differences in the organ development observed in the individual knockout mice result from isoform-specific functions or quantitative differences in the expression levels of each STAT5 isoform among tissues. To elucidate the redundancy and isoform-specificity of STAT5 for development at molecular levels, mice carrying only a single allele of either Stat5a or Stat5b were generated. Both of these mice overcame the lethal anemia observed in Stat5ab-null mice, indicating that development of erythroid cell lineage was totally dependent on the dosage of STAT5. The blocked progression of B cell lineage at the pre-pro B cell stage in Stat5ab-/- mice was rescued in the presence of a single allele of either Stat5a or Stat5b, while the number of total B220+ cells in bone marrow was smaller in Stat5abnull/Stat5b- mice than Stat5abnull/Stat5a- mice. The paucity of alveolar progenitor cells in the Stat5ab-null mammary epithelium was rescued by a single allele of either Stat5a but not Stat5b, suggesting cell-type dependent isoform-specific function. Genome-wide gene expression analyses revealed that different steps of cell lineage progression require different gene sets which expression requires the different isoform of STAT5 in a dose-dependent manner in the mammary epithelium. Taken together, this study demonstrates that dose-dependent isoform specificity of STAT5A and STAT5B controls progression and differentiation of each cell lineage. Six days after observation of a plug, mammary tissues from three of each Stat5a-/- mice, Stat5ab+/null mice, Stat5abnull/Stat5b- and Stat5abnull/Stat5a- mice were collected, frozen in liquid nitrogen, and stored at -70 °C

2012-04-30 | E-GEOD-29045 | biostudies-arrayexpress

Impact of STAT5 dosage and binding location on genetic and biological programs activated in mouse mammary epithelium during pregnancy.

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

WGD paralog evolution

Project description:WGD paralog evolution

| PRJNA743682 | ENA

A Potent and Selective Small-Molecule STAT5 PROTAC Degrader Capable of Achieving Tumor Regression In Vivo

Project description:We have developed AK2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. To investigate the effect of STAT5A/STAT5B depletion on the transcriptome, we treated KU812 and NCO2 cells with AK2292 at 1 μM for 8 h and performed RNA-seq analysis. As a control, we treated KU812 and NCO2 cells with AK2292Me at 5 μM for 24 h for RNA-seq analysis. RNA-seq analysis revealed that AK2292 downregulates the transcriptome associated with STAT5A and STAT5B.

2022-12-15 | GSE217647 | GEO

Identification of Stat5 Target Genes by siRNA-mediated knockdown

Project description:STAT5A and STAT5B proteins belong to the family of signal transducers and activators of transcription. They are encoded by 2 separate genes with 91% identity in their amino acid sequences. Despite their high degree of conservation, STAT5A and STAT5B exert non-redundant functions, resulting at least in part from differences in target gene activation. To better characterize the differential contribution of STAT5A and STAT5B in gene regulation, we performed single or double knock-down of STAT5A and STAT5B using small interfering RNA. Subsequent gene expression profiling and RT-qPCR analyses of IL-3-stimulated Ba/F3-beta cells led to the identification of putative novel STAT5 target genes. Chromatin immunoprecipitation assays analyzing the corresponding gene loci identified unusual STAT5 binding sites compared to conventional STAT5 responsive elements. Some of the STAT5 targets identified are upregulated in several human cancers, suggesting that they might represent potential oncogenes in STAT5-associated malignancies. Keywords: siRNA-mediated knock-down

2008-06-23 | GSE10389 | GEO

Genetic modification of STAT5 levels reveals dose-dependent and isoform-specific requirement for cell lineage progression and differentiation.

2012-05-01 | GSE29045 | GEO

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