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

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

PROVIDER: PRJNA678955 | ENA |

REPOSITORIES: ENA

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Redundant and non-redundant cytokine-activated enhancers control Csn1s2b expression in the lactating mouse mammary gland.

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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.

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Evolutionary transition from degenerate to non-redundant cytokine signaling networks supporting intrathymic T cell development

Project description:In mammals, T cell development in the thymus is critically dependent on the presence of the IL7 cytokine. Here, we describe the identification of the zebrafish ortholog of mammalian IL7, based on chromosomal localization, expression patterns, and deduced protein sequence. To examine the biological role of il7 in teleosts, we generated an il7 allele lacking most of its coding exons using CRISPR/Cas9-based mutagenesis. il7-deficient animals are viable, and exhibit no obvious signs of immune disorder. With respect to intrathymic T cell development, il7-deficiency is associated with only mild a reduction of thymocytes, contrasting with the much stronger reduction of T cell development il7r-deficient fish. Genetic interaction studies between il7 and crlf2(tslpr) suggest the contribution of an additional, as yet unidentified cytokine(s) to intrathymic T cell development. Such activities were also ascertained for other cytokines, such as il2 and il15, collectively indicating that, in contrast to the situation in mammals, T cell development in the thymus of teleosts is driven by a degenerate multi-component network of gc cytokines. This network configuration thus explains why deficiencies of single components have little detrimental effect. By contrast, the dependence on a single cytokine in the mammalian thymus has catastrophic consequences in case of congenital deficiencies in genes affecting the IL7 signaling pathway. We speculate that the transition from a degenerate to a non-redundant cytokine network supporting intrathymic T cell development emerged as the consequence of repurposing evolutionary ancient constitutive cytokine pathways for regulatory functions in the mammalian peripheral immune system.

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Evolutionary transition from degenerate to non-redundant cytokine signaling networks supporting intrathymic T cell development

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Functional assessment of CTCF sites at cytokine-sensing mammary enhancers in mammary gland [4C-seq]

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Project description:Functional analysis of CTCF sites associated with cytokine-sensing mammary-specific enhancers in the complex casein locus

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Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling.

Project description: Not available

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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

Cytokine-sensing primary enhancer cluster launches secondary enhancers to activate multi-gene locus

Project description:Cytokine-sensing primary enhancer cluster launches secondary enhancers to activate multi-gene locus

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Functional analysis of CTCF sites associated with cytokine-sensing mammary-specific enhancers in the complex casein locus

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-03-24 | GSE95758 | GEO