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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE84115 | GEO | 2016/09/12

SECONDARY ACCESSION(S): PRJNA328052

REPOSITORIES: GEO

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Mus musculus

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

| PRJNA328052 | ENA

Hierarchy within the mammary STAT5-driven Wap super-enhancer

Project description:Super-enhancers comprise of dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate their role in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-Seq for the master regulator STAT5, the glucocorticoid receptor, H3K27ac and MED1, identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5 binding sites within its three constituent enhancers. Individually, only the most distal site displayed significant enhancer activity. However, combinatorial mutations showed that the 1,000-fold gene induction relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer, suggesting an enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insight into the complexity of cell-specific and hormone-regulated genes. ChIP-Seq for STAT5A, GR, H3K27ac, MED1, NFIB, ELF5, RNA Pol II, and H3K4me3 in wild type (WT) mammary tissues at day one of lactation (L1), and ChIP-Seq for STAT5A, GR, H3K27ac, MED1, NFIB, ELF5, and H3K4me3 in WT mammary tissues at day 13 of pregnancy (p13). ChIP-Seq for STAT5A, GR, H3K27a in Wap-delE1a, -delE1b, -delE1c, -delE2 and -delE3 mutant mammary tissues at L1, and ChIP-Seq for NFIB and ELF5 in Wap-delE1b and -delE1c mutant mammary tissues at L1. ChIP-Seq for H3K4me3 in mammary-epthelial cells at p13 and L1. DNase-seq in WT mammary tissues at L1 and DNase-seq in Wap-delE1a, -delE1c, and -delE3 mutant mammary tissues at L1.

2016-05-31 | E-GEOD-74826 | biostudies-arrayexpress

An autoregulatory enhancer controls mammary-specific STAT5 functions

Project description:Signal Transducers and Activators of Transcription (STATs) are principal transcription factors downstream of cytokine receptors. Although STAT5A is expressed in most tissues it remains to be understood why its premier, non-redundant functions are restricted to prolactin-induced mammary gland development. We report that the ubiquitously expressed Stat5a/b locus is subject to lineage-specific transcriptional control in mammary epithelium. Genome-wide surveys of epigenetic status and transcription factor occupancy uncovered a putative mammary-specific enhancer within the intergenic sequences separating the two Stat5 genes. This region exhibited several hallmarks of genomic enhancers, including DNaseI hypersensitive sites, H3K27 acetylation and binding by GR and MED1. Mammary-specific STAT5 binding was obtained at two canonical STAT5 binding motifs. CRISPR/Cas9-mediated genome editing was used to delete these STAT5 binding sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels in mammary epithelium and a concomitant reduction of STAT5-dependent gene expression. Transcriptome analysis identified a class of mammary-restricted genes that was particularly dependent on high STAT5 levels as a result of the intergenic enhancer. Taken together, the mammary-specific enhancer enables a positive feedback circuit that underlies the remarkable abundance of STAT5 and, in turn, controls the efficacy of STAT5-dependent mammary physiology. ChIP-seq for H3K27ac, RNA Pol II, and MED1 in mammary tissues at L1, and ChIP-seq for H3K27ac and GR in mammary tissues at p13. mRNA-seq in WT at L1, line B (GAS2 mutation only) and line C (both GAS1 and GAS2 mutations) at L1 in mammary tissues, and DNase-seq in WT mammary tissues at L1.

2015-09-05 | E-GEOD-72724 | biostudies-arrayexpress

An autoregulatory enhancer controls mammary-specific STAT5 functions

2015-09-05 | GSE72724 | GEO

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

Project description: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.

2016-12-20 | GSE82275 | GEO

Hierarchy within the mammary STAT5-driven Wap super-enhancer

2016-05-31 | GSE74826 | GEO

MiR-21 is targeted by STAT5 but dispensable for mammary gland development

Project description:In this study we identifies miR-21 to by under cytokine control through the transcription factor STAT5 and while miR-21 is differentially expressed during mammary gland development, miR-21 is dispensable for mammary development and lactation.

2013-08-22 | GSE50068 | GEO

MiR-21 is targeted by STAT5 but dispensable for mammary gland development

2013-08-22 | E-GEOD-50068 | biostudies-arrayexpress

EZH2 controls mammary differentiation independently of its methyltransferase activity through controlling genomic STAT5 access

Project description:Mammary development is characterized by the proliferation and progressive differentiation of alveolar epithelium during pregnancy, culminating in lactation. These processes are largely controlled by hormones through transcription factors. We now explore the contributions of histone methyltransferases, which establish H3K27me3 marks, in the temporally-regulated differentiation of mammary epithelium. Loss of EZH2, but not EZH1, resulted in precocious mammary differentiation, which was facilitated by STAT5 binding to specific target genes and their activation. Mammary stem cells were not compromised in the absence of EZH2. Genome-wide H3K27me3 patterns remained intact in the absence of EZH2. Mammary-specific loci were devoid of H3K27me3 marks in mammary progenitor and mature cells, suggesting no regulatory role for this repressive mark. Lastly, the combined absence of EZH1 and EZH2 inhibited the formation of alveoli. Taken together, EZH2 controls temporally-restricted differentiation of mammary epithelium through H3K27me3-independent mechanisms. mRNA-seq and ChIP-seq in MMTV-Cre (Control), E1-/- (E1KO), E1+/-;E2f/f;control (E1+/-E2KO) and Ezh2f/f;control (E2KO) mammary gland tissues or MECs (purified mammary epithelial cells). H3K27me3 and STAT5 ChIP-seqs in mammary tissues at p13; H3K4me3 ChIP-seq in MECs (mammary epithelial cells) at p13; RNA-seqs at mature virgin (with/without prolactin injection), p13 and p18 mammary tissues.

2013-12-31 | E-GEOD-52016 | biostudies-arrayexpress

Functional dissection of the Csn1s2b locus identifies complex redundant and non-redundant cytokine-activated enhancers in mouse mammary gland tissue

Project description:Enhancers are transcription factor platforms that synergize with promoters to activate gene expression. While genome-wide chromatin studies can predict enhancers, only experimental genetics can reveal their in vivo significance and the respective contribution of individual transcription factors. Here we investigate the regulation of the Csn1s2b gene whose expression in the mouse mammary gland is induced several thousand-fold during pregnancy and lactation. Using ChIP-seq for activating histone marks and transcription factors, we identified candidate enhancers distal to the promoter and within an intron and one super-enhancer separated from the Csn1s2b gene by the Prr27 gene. Using experimental mouse genetics, we dissected the complex lactation-specific distal enhancer bound by the prolactin-activated transcription factor STAT5 and the mammary-enriched NFIB and the glucocorticoid receptor. Deletion of the canonical binding motifs for NFIB and STAT5, individually and combined, had a limited biological impact. Additional deletions revealed the importance of a non-canonical STAT5 binding site for enhancer activity throughout lactation. In contrast, the intronic enhancer activated gene expression only in late pregnancy and early lactation, likely by interacting with the distal enhancer. A downstream super-enhancer, which physically interacts with the distal enhancer, was required for the functional establishment of the Csn1s2b promoter and gene activation. Lastly, NFIB binding in the promoter region fine-tuned Csn1s2b expression. Our study provides comprehensive insight into the anatomy and biology of regulatory elements spanning 70 bp that employ the JAK/STAT signaling pathway and activate gene expression several hundred-fold during lactation.

2021-02-11 | GSE161620 | GEO

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