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Cell-specific and shared regulatory elements control a multi-gene locus active in mammary and salivary glands [Bisulfite-seq]

ABSTRACT: Regulation of high-density loci harboring genes with different cell-specificities remains a puzzle. Here we investigate a locus that evolved through gene duplication and contains eight genes and 20 candidate regulatory elements, including one super-enhancer. Five genes (Csn1s1, Csn2, Csn1s2a, Csn1s2b, Csn3) are expressed in mammary glands and account for 50% of mRNAs during lactation, two (Prr27, Fdcsp) are salivary-specific and one (Odam) has dual specificity. We probed the function of 12 candidate control elements, individually and in combination, in the mouse genome. The super-enhancer is essential for the expression of Csn3, Odam and Fdcsp but largely dispensable for Csn1s1, Csn2 and Csn1s2a. Csn3 activation also requires its own local enhancer. Synergism between local enhancers and cytokine-responsive promoter elements facilitated the 10,000-fold activation of Csn2 during pregnancy. Our work identifies regulatory complexity of a multigene locus with an ancestral super-enhancer active in mammary and salivary tissue and local enhancers and promoter elements.

ORGANISM(S): Mus musculus

PROVIDER: GSE231438 | GEO | 2023/07/28

REPOSITORIES: GEO

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Cell-specific and shared regulatory elements control a multi-gene locus active in mammary and salivary glands [ChIP-Seq]

Project description:Regulation of high-density loci harboring genes with different cell-specificities remains a puzzle. Here we investigate a locus that evolved through gene duplication and contains eight genes and 20 candidate regulatory elements, including one super-enhancer. Five genes (Csn1s1, Csn2, Csn1s2a, Csn1s2b, Csn3) are expressed in mammary glands and account for 50% of mRNAs during lactation, two (Prr27, Fdcsp) are salivary-specific and one (Odam) has dual specificity. We probed the function of 12 candidate control elements, individually and in combination, in the mouse genome. The super-enhancer is essential for the expression of Csn3, Odam and Fdcsp but largely dispensable for Csn1s1, Csn2 and Csn1s2a. Csn3 activation also requires its own local enhancer. Synergism between local enhancers and cytokine-responsive promoter elements facilitated the 10,000-fold activation of Csn2 during pregnancy. Our work identifies regulatory complexity of a multigene locus with an ancestral super-enhancer active in mammary and salivary tissue and local enhancers and promoter elements.

2023-07-28 | GSE231439 | GEO

Cell-specific and shared regulatory elements control a multi-gene locus active in mammary and salivary glands [RNA-Seq]

2023-07-28 | GSE231440 | GEO

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

Project description:The zinc finger protein CTCF has been invoked in establishing functional boundaries between genes and thereby controlling enhancer activities. However, there is limited genetic evidence to support such a concept. We have now addressed this question in a locus containing five mammary-specific genes controlled by enhancers. We have identified four CTCF binding sites in the casein locus, two at the outside boundaries and two associated with a super-enhancer. Individual deletions of these sites from the mouse genome did not alter expression of the five casein genes and Odam. However, deletion of the border CTCF site separating the Csn1s1 enhancer from non-mammary genes resulted in the activation of Sult1d1 at a distance of more than 95 kb but not the more proximal Sult1e1 gene. Loss of this CTCF site led to de novo interactions between the Csn1s1 enhancer and the Sult1d1 promoter but not with the silent Sult1e1 gene. Our study suggests that most CTCF sites associated with cell-specific enhancers and super-enhancers have no measurable in vivo activity. Only the loss of one CTCF site led to the induction of a juxtaposed active non-target promoter. Our study also demonstrated that cell-specific enhancers are unable to activate juxtaposed silent non-target promoters.

2017-03-24 | GSE92591 | GEO

Impact of CSN1S1 polymorphism on mammary transcriptome of lactating goats

Project description:Genetic (animal species, breed and genotype) has a considerable effect on milk composition. In particular, goats present a remarkable polymorphism at the alpha-S1-casein (CSN1S1) locus which results in large differences in milk protein content and indirectly in milk fat content and its fatty acids composition. In order to decipher the mammary metabolic pathways involved, we examined the effect of CSN1S1 polymorphism on the expression of 8,379 genes in caprine mammary gland using a bovine oligonucleotide microarray. Six lactating goats fed ad libitum were assigned to 2 groups based on their genotype at the CSN1S1 locus: High vs. Low genotype goats carrying, respectively, two reference alleles associated with high CSN1S1 synthesis and two defective alleles associated with low CSN1S1 synthesis. Keywords: Genotype comparison 6 slides were performed for a total of 3 independent comparisons (Comp1, Comp2, Comp3): each microarray was co-hybridized with one High CSN1S1 genotype goat sample and one Low CSN1S1 genotype goat sample; each hybridization was repeated in a dye-swap manner for a total of 4 spots per oligonucleotide (2 intra- and 2 inter-slides).

2010-05-27 | E-GEOD-6637 | biostudies-arrayexpress

Impact of CSN1S1 polymorphism on mammary transcriptome of food-deprived lactating goats

Project description:Genetic (animal species, breed and genotype) has a considerable effect on milk composition. In particular, goats present a remarkable polymorphism at the alpha-S1-casein (CSN1S1) locus which results in large differences in milk protein content and indirectly in milk fat content and its fatty acids composition. In order to decipher the mammary metabolic pathways involved, we examined the effect of CSN1S1 polymorphism on the expression of 8,379 genes in caprine mammary gland using a bovine oligonucleotide microarray. Six 48-h food-deprived lactating goats were assigned to 2 groups based on their genotype at the CSN1S1 locus: High vs. Low genotype goats carrying, respectively, two reference alleles associated with high CSN1S1 synthesis and two defective alleles associated with low CSN1S1 synthesis. Keywords: Genotype comparison 6 slides were performed for a total of 3 independent comparisons (CompA, CompB, CompC): each microarray was co-hybridized with one High CSN1S1 genotype goat sample and one Low CSN1S1 genotype goat sample; each hybridization was repeated in a dye-swap manner for a total of 4 spots per oligonucleotide (2 intra- and 2 inter-slides).

2008-01-02 | E-GEOD-6642 | biostudies-arrayexpress

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

Project description:In mammary gland, deletion of the border CTCF site separating the Csn1s1 mammary enhancer from neighboring genes resulted in the activation of Sult1d1 at a distance of more than 95 kb but not the more proximal and silent Sult1e1 gene. Loss of this CTCF site led to de novo interactions between the Sult1d1 promoter and several enhancers in the casein locus.

2017-03-24 | GSE95757 | GEO

Impact of CSN1S1 polymorphism on mammary transcriptome of lactating goats

2008-01-03 | GSE6637 | GEO

Impact of CSN1S1 polymorphism on mammary transcriptome of food-deprived lactating goats

Project description:Genetic (animal species, breed and genotype) has a considerable effect on milk composition. In particular, goats present a remarkable polymorphism at the alpha-S1-casein (CSN1S1) locus which results in large differences in milk protein content and indirectly in milk fat content and its fatty acids composition. In order to decipher the mammary metabolic pathways involved, we examined the effect of CSN1S1 polymorphism on the expression of 8,379 genes in caprine mammary gland using a bovine oligonucleotide microarray. Six 48-h food-deprived lactating goats were assigned to 2 groups based on their genotype at the CSN1S1 locus: High vs. Low genotype goats carrying, respectively, two reference alleles associated with high CSN1S1 synthesis and two defective alleles associated with low CSN1S1 synthesis. Keywords: Genotype comparison

2008-01-03 | GSE6642 | GEO

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

Facultative CTCF sites moderate mammary super-enhancer activity and regulate juxtaposed gene in non-mammary cells [4C-seq]

Project description:Precise spatiotemporal regulation of genetic programs, driven by cellspecific super-enhancers, is paramount for the function of cell lineages. Studies have suggested that insulated neighborhoods, formed by the zincfinger protein CTCF, sequester genes and their associated enhancers thus preventing them from trespassing on off-target genes. Although this could explain the enhancer-gene-specificity conundrum, there is limited genetic evidence that the search space of cell-specific super-enhancers is constrained by CTCF. We have addressed this question in the Wap locus with its exceptional mammary-specific super-enhancer, which is separated by five CTCF sites from neighboring genes. Three of these sites are positioned between the Wap super-enhancer and the widely expressed Ramp3. Enhancer deletions demonstrated that the Wap super-enhancer controls Ramp3 expression despite the presence of three parting CTCF sites. Individual and combinatorial deletions of these CTCF sites revealed cell-specific functions of the conserved anchor site. Although unable to block super-enhancer activity, it muffled its impact on Ramp3 in mammary tissue. Unexpectedly, this CTCF site was obligatory for Ramp3 expression in cerebellum, suggesting the coinciding presence of regulatory elements. While our results suggest a surprisingly limited in vivo role for a CTCF anchor in blocking a mammary-specific super-enhancer, they also implicate this site in cerebellum-specific gene activation. Our study illustrates additional complexities of CTCF sites supporting tissue-specific functions.

2017-05-25 | GSE97803 | GEO

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