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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE231441 | GEO | 2023/07/28

REPOSITORIES: GEO

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Cell-specific and shared regulatory elements control a multigene locus active in mammary and salivary glands.

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. Casein genes (Csn1s1, Csn2, Csn1s2a, Csn1s2b, Csn3) are expressed in mammary glands, induced 10,000-fold during pregnancy and account for 50% of mRNAs during lactation, Prr27 and Fdcsp are salivary-specific and Odam has dual specificity. We probed the function of 12 candidate regulatory elements, individually and in combination, in the mouse genome. The super-enhancer is essential for the expression of Csn3, Csn1s2b, 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 facilitates activation of Csn2 during pregnancy. Our work identifies the regulatory complexity of a multigene locus with an ancestral super-enhancer active in mammary and salivary tissue and local enhancers and promoter elements unique to mammary tissue.

| S-EPMC10435465 | biostudies-literature

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]

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 | GSE231440 | GEO

Cell-specific and shared regulatory elements control a multi-gene locus active in mammary and salivary glands [Bisulfite-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 | GSE231438 | GEO

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

Project description:Cell-specific and shared regulatory elements control a multi-gene locus active in mammary and salivary glands

| PRJNA965824 | ENA

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

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

| PRJNA965827 | ENA

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

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

| PRJNA965828 | ENA

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

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

| PRJNA965829 | ENA

Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis.

Project description:The SMARCA4 (also known as BRG1 in humans) chromatin remodeling factor is critical for establishing lineage-specific chromatin states during early mammalian development. However, the role of SMARCA4 in tissue-specific gene regulation during embryogenesis remains poorly defined. To investigate the genome-wide binding landscape of SMARCA4 in differentiating tissues, we engineered a Smarca4(FLAG) knock-in mouse line. Using ChIP-seq, we identified ∼51,000 SMARCA4-associated regions across six embryonic mouse tissues (forebrain, hindbrain, neural tube, heart, limb, and face) at mid-gestation (E11.5). The majority of these regions was distal from promoters and showed dynamic occupancy, with most distal SMARCA4 sites (73%) confined to a single or limited subset of tissues. To further characterize these regions, we profiled active and repressive histone marks in the same tissues and examined the intersection of informative chromatin states and SMARCA4 binding. This revealed distinct classes of distal SMARCA4-associated elements characterized by activating and repressive chromatin signatures that were associated with tissue-specific up- or down-regulation of gene expression and relevant active/repressed biological pathways. We further demonstrate the predicted active regulatory properties of SMARCA4-associated elements by retrospective analysis of tissue-specific enhancers and direct testing of SMARCA4-bound regions in transgenic mouse assays. Our results indicate a dual active/repressive function of SMARCA4 at distal regulatory sequences in vivo and support its role in tissue-specific gene regulation during embryonic development.

| S-EPMC4032856 | biostudies-literature

Cell-Specific Cre Strains For Genetic Manipulation in Salivary Glands.

Project description:The secretory acinar cells of the salivary gland are essential for saliva secretion, but are also the cell type preferentially lost following radiation treatment for head and neck cancer. The source of replacement acinar cells is currently a matter of debate. There is evidence for the presence of adult stem cells located within specific ductal regions of the salivary glands, but our laboratory recently demonstrated that differentiated acinar cells are maintained without significant stem cell contribution. To enable further investigation of salivary gland cell lineages and their origins, we generated three cell-specific Cre driver mouse strains. For genetic manipulation in acinar cells, an inducible Cre recombinase (Cre-ER) was targeted to the prolactin-induced protein (Pip) gene locus. Targeting of the Dcpp1 gene, encoding demilune cell and parotid protein, labels intercalated duct cells, a putative site of salivary gland stem cells, and serous demilune cells of the sublingual gland. Duct cell-specific Cre expression was attempted by targeting the inducible Cre to the Tcfcp2l1 gene locus. Using the R26Tomato Red reporter mouse, we demonstrate that these strains direct inducible, cell-specific expression. Genetic tracing of acinar cells using PipGCE supports the recent finding that differentiated acinar cells clonally expand. Moreover, tracing of intercalated duct cells expressing DcppGCE confirms evidence of duct cell proliferation, but further analysis is required to establish that renewal of secretory acinar cells is dependent on stem cells within these ducts.

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