Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Lineage-specific and non-specific cytokine-sensing genes respond differentially to the master regulator STAT5

ABSTRACT: STAT5, a member of the family of Signal Transducers and Activators of Transcription senses cytokines and controls the biology of cell lineages, including mammary, liver and T cells. Here we show that STAT5 activates lineage-specific and widely expressed genes through different mechanisms. STAT5 preferentially binds to promoter sequences of cytokine-responsive genes expressed across cell types and to putative enhancers of lineage-specific genes. While chromatin accessibility of STAT5-based enhancers was dependent on cytokine exposure, STAT5-responsive promoters of widely expressed target genes were generally constitutively accessible. While the contribution of STAT5 to enhancers is well established, its role on promoters is poorly understood. To address this we focused on Socs2, a widely expressed cytokine-sensing gene. Upon deletion of the STAT5 response elements from the Socs2 promoter, cytokine induction was abrogated, while basal activity remained intact. Our data suggest that promoter-bound STAT5 modulates cytokine responses and enhancer-bound STAT5 is mandatory for gene activation.

ORGANISM(S): Mus musculus

PROVIDER: GSE82275 | GEO | 2016/12/20

SECONDARY ACCESSION(S): PRJNA324535

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Genome-wide analyses reveal the extent of opportunistic STAT5 binding that does not yield transcriptional activation of neighboring genes.

Project description:Signal Transducers and Activators of Transcription (STAT) 5A/B regulate cytokine-inducible genes upon binding to GAS motifs. It is not known what percentage of genes with GAS motifs bind to and are regulated by STAT5. Moreover, it is not clear whether genome-wide STAT5 binding is modulated by its concentration. To clarify these issues we established genome-wide STAT5 binding upon growth hormone (GH) stimulation of wild type mouse embryonic fibroblasts (MEFs) and MEFs overexpressing STAT5A more than 20-fold. Upon GH stimulation 23,827 and 111,939 STAT5A binding sites were detected in wild type and STAT5A overexpressing MEFs, respectively. 13,278 and 71,561 peaks contained at least one GAS motif. 1,586 and 8,613 binding sites were located within 2.5 kbp of promoter sequences, respectively. Stringent filtering revealed 78 genes in which the promoter/upstream region (-10kbp to +0.5kbp) was recognized by STAT5 both in wt and STAT5 overexpressing MEFs and 347 genes that bound STAT5 only in overexpressing cells. Genome-wide expression analyses identified that the majority of STAT5-bound genes was not under GH control. Up to 40% of STAT5-bound genes were not expressed. For the first time we demonstrate the magnitude of opportunistic genomic STAT5 binding that does not translate into transcriptional activation of neighboring genes. Genome-wide mapping of STAT5 binding in MEF cells (WT, KO; Stat5-/- and overexpression; STAT5A-Stat5-/-) upon growth hormone induction

2012-01-12 | E-GEOD-34986 | biostudies-arrayexpress

Constitutively active STAT5 recruits p53 to alternative transcriptional targets in myeloid cancers

Project description:In several cancer types, STAT (Signal transducer and activator of transcription) transcription factors are constitutively activated. We previously identified a target gene, LPP/miR-28 (LIM domain containing preferred translocation partner in lipoma), induced by constitutive activation of STAT5, but not by transient cytokine-activated STAT5. Here, we demonstrate in transformed hematopoietic cells that binding of both STAT5B and p53 to chromatin is required for transcriptional activity of an alternative LPP/miR-28 promoter. Using a genome-wide approach, we identified 463 genomic positions at promoter regions where STAT5B and p53 are co-localized on the chromatin. At these positions, p53 chromatin binding is dependent on persistent STAT5B activation. The transcriptional activity of selected promoters bound by STAT5B and p53 was significantly changed upon STAT5 or p53 inhibition, and the transcription of these target genes is frequently altered in platelets of myeloproliferative neoplasm patients harboring mutations constitutively activating STAT5. These data suggest that the constitutive STAT5 activation recruits p53 in cancer cells and thereby activates oncogenic transcriptional programs. STAT5B and p53 ChIP-chip with or without JAK2 inhibition (ruxolitinib) to inhibit STAT5 phosphorylation and DNA binding.

2014-02-01 | E-GEOD-38143 | biostudies-arrayexpress

Differential cytokine sensitivities of mammary-specific and universal STAT5 enhancers depends on Stat5 autoregulation

Project description:Cytokines utilize the transcription factor STAT5 to control cell-specific and universal genes. In general, the magnitude of cell-restricted gene activation greatly exceeds that of universal genes, with a mechanistic explanation yet to be supplied. Genome-wide studies have identified putative STAT5-based mammary-specific enhancers and universal STAT5-controlled regulatory elements, an opportunity to investigate mechanisms underlying their differential response to cytokines. We have now interrogated the integrity and function of both categories of regulatory elements using biological and genetic approaches. During lactation, STAT5 occupies mammary-specific and universal cytokine-responsive elements. Following lactation, prolactin levels decline and STAT5-dependent enhancers at mammary-specific genes are decommissioned with 24 hours while universal regulatory complexes remain intact. These differential sensitivities are linked to STAT5 concentrations and the mammary-specific Stat5 autoregulatory enhancer. In its absence, mammary-specific enhancers, but not universal elements, fail to be fully established. Upon termination of lactation, STAT5 binding to a subset of mammary enhancers is substituted by STAT3. No STAT3 binding was observed at the most sensitive STAT5 enhancers, suggesting that upon hormone withdrawal their chromatin becomes inaccessible. This study, for the first time, provides molecular insight into the differential sensitivities of mammary-specific and universal cytokine-sensing enhancers.

2016-09-12 | GSE84115 | GEO

Genome-wide analyses reveal the extent of opportunistic STAT5 binding that does not yield transcriptional activation of neighboring genes.

2012-01-12 | GSE34986 | GEO

Progressing enhancer landscape during mammary differentiation controls gene regulation [RNA-seq]

Project description:The mammary luminal lineage relies on the common cytokine-sensing transcription factor STAT5 to establish super-enhancers during pregnancy and activate mammary genes required for the nutrition of the offspring. Exploiting progressive differentiation during lactation, we investigated how hormonal cues shape an evolving enhancer landscape and impact the biology of mammary cells. Employing ChIP-seq, we uncover a changing transcription factor occupancy at mammary enhancers. Using mouse genetics, we demonstrate changing biological properties of enhancers as lactation progresses, with individual enhancers gaining strength and an abolished need for the Wap seed enhancer. We further investigated whether permissive chromatin facilitates cell-specific transcription factor binding. Wap enhancers translocated into the widely expressed neighboring Ramp3 gene retained their mammary-specificity and failed to activate the receptive Ramp3 gene in non-mammary tissues. Our studies unveil a previously unrecognized progressive enhancer landscape, in which structurally equivalent components serve unique and differentiation-specific functions. While enhancer redundancy has been suggested and demonstrated for many genes, components of the cytokine-responsive mammary tripartite Wap super-enhancer display a remarkable specificity.

2018-09-18 | GSE115369 | GEO

Progressing enhancer landscape during mammary differentiation controls gene regulation [ChIP-seq]

2018-09-18 | GSE115368 | GEO

Genome wide analysis of SOCS2 dependent gene expression profile in bone marrow LSK following 5-Fluorouracil treatment

Project description:Hematopoietic stem cells (HSC) promptly adapt hematopoiesis to stress conditions, such as infection and cancer, by replenishing bone marrow (BM)-derived circulating populations while preserving the stem cell reservoir. SOCS2, a feedback inhibitor of JAK/STAT pathways is expressed in most primitive HSC and is upregulated in response to STAT5-inducing cytokines. We demonstrate that Socs2 deficiency unleashes HSC proliferation in vitro sustaining STAT5 phosphorylation in response to the hematopoietic cytokines IL-3, thrombopoietin (TPO) and GM-CSF. In vivo, SOCS2 deficiency leads to unrestricted myelopoietic response to 5-fluorouracil and, in turn, induces exhaustion of long-term HSC function along serial BM transplantations. These findings unveiled a new regulatory role for SOCS2 in normalizing HSC functions under hematopoietic stress and prompted its investigation for involvement in malignant hematopoiesis. Indeed, in acute myeloid and lymphoblastic leukemias high levels of SOCS2 characterize unfavorable subclasses with MLL and BCR/ABL abnormalities. Analysis of gene expression profiles showed that high SOCS2 positively correlates with a pool of genes that are significatively enriched of members of the stemness signature described in acute myeloid leukemia. Unexpectedly, in acute leukemias, SOCS2 and its related genes are not controlled by STAT5 signaling, they are rather part of regulatory networks fronted by IKZF1/Ikaros and MEF2C, two key hematopoietic stemness-related transcriptional factors that, independently, have been described in leukemias but never linked together in controlling SOCS2 expression and unfavorable leukemia outcome.

2015-06-01 | GSE66065 | GEO

Constitutively active STAT5 recruits p53 to alternative transcriptional targets in myeloid cancers

2014-02-01 | GSE38143 | GEO

Mus musculus

Project description:Differential cytokine sensitivities of mammary-specific and universal STAT5 enhancers depends on Stat5 autoregulation

| PRJNA328052 | ENA

Strong Activation of Retroviral LTRs in HCC

Project description:<p>The ncRNA transcriptome of human hepatocellular carcinoma (HCC) is largely unexplored. We used CAGE to characterize transcription start sites across different etiologies of human HCCs with emphasis on ncRNAs. Here we report that retroviral LTR promoters, expressed in healthy tissues such as testis and placenta but not liver, are widely activated in HCC. Despite HCC heterogeneity, a subset of LTR-derived ncRNAs were more than 10-fold up-regulated in the vast majority of samples. HCCs with a high LTR activity mostly had a viral etiology, were less differentiated and showed higher risk of recurrence. CAGE enabled us to build a promoter map for HCC, which uncovers a new layer of complexity in HCC genomics.</p>

| phs000885 | dbGaP

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data