MiR-21 is targeted by STAT5 but dispensable for mammary gland development
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: 
Lothar Hennighausen Keunsoo Kang Yonatan Feuermann
PROVIDER: E-GEOD-50068 | ArrayExpress | 2013-08-22
SECONDARY ACCESSION(S): GSE50068SRP028970PRJNA215937
REPOSITORIES: GEO, ArrayExpress, ENA
Dataset's files
primary
| Action | DRS | |||
|---|---|---|---|---|
| E-GEOD-50068.BAM.SRR955011.bam | Bam | |||
| E-GEOD-50068.BAM.SRR955011.bam.bai | Bam | |||
| E-GEOD-50068.BAM.SRR955011.bam.prop | Bam | |||
| E-GEOD-50068.BAM.SRR955012.bam | Bam | |||
| E-GEOD-50068.BAM.SRR955012.bam.bai | Bam |
Items per page: 5 1 - 5 of 15 |
Similar Datasets
Project description:Establishment and differentiation of mammary alveoli during pregnancy are controlled by prolactin through the transcription factor STAT5. As pregnancy progresses mammary signature genes are activated in a defined temporal order, which coincides with the recruitment of STAT5 to respective regulatory sequences. This study addressed the question whether the methyltransferase and transcriptional co-activator EZH2 controls the differentiation clock of mammary epithelium. Ablation of Ezh2 from mammary stem cells resulted in precocious differentiation of alveolar epithelium during pregnancy and the activation of mammary-specific STAT5 target genes. This coincided with enhanced occupancy by STAT5, EZH1 and Pol II to these loci. Limited activation of differentiation-specific genes was also observed in mammary epithelium lacking both EZH2 and STAT5, suggesting a modulating but not mandatory role for STAT5. Notably, loss of EZH2 did not result in overt changes in genome-wide and gene-specific H3K27me3 patterns, suggesting that enhanced EZH1 recruitment can compensate for the loss of EZH2. Differentiated mammary epithelia failed to form in the combined absence of EZH1 and EZH2. Transplantation experiments failed to demonstrate a role for EZH2 in the biology of mammary stem and progenitor cells. In summary, while EZH1 and EZH2 serve redundant functions in the establishment of H3K27me3 and formation of mammary alveoli, the presence of EZH2 is required to obtain controlled temporal differentiation of mammary epithelium. mRNA-seq in WT;MMTV-Cre (Control) at p13 and p18, E1-/- (E1KO), Ezh2f/f;MMTV-Cre(E2KO), Stat5f/f;MMTV-Cre(S5KO), and Ezh2f/f;Stat5f/f;MMTV-Cre (E2S5DKO) at p13 mammary tissues. ChIP-seq for H3K27me3, STAT5, EZH1, EZH2 and PolII in mammary tissues at p13
2015-08-31 | E-GEOD-70440 | ArrayExpress
Project description:To dissect regulatory processes of cell proliferation and differentiation we generated mouse strains carrying any combination of the four Stat5 alleles, thus expressing STAT5 from 0 to 100%. RNA-Seq analyses revealed that different STAT5 levels activate specific genetic programs linked to cell proliferation and differentiation. We refer to wild-type mice and Stat5abfl/fl mice as AABB mice; Stat5abfl/fl;MMTV-Cre (with Stat5ab-deficient mammary epithelial cells) as Null mice; Stat5a-/- mice as BB mice; Stat5b-/- mice as AA mice; Stat5ab+/null mice as AB mice.
2012-05-02 | E-GEOD-37646 | ArrayExpress
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. We refer to wild-type mice (+/+) as WT and to mice lacking the mir-21 (-/-) as KO mice.
2013-08-22 | E-GEOD-50068 | BioStudies
Project description:Development of mammary alveolar epithelium during pregnancy is controlled by prolactin, through the transcription factors STAT5A/B that activate specific sets of target genes. Here we asked whether some of STAT5's functions are mediated by microRNAs. The miR-21 promoter sequence contains a bona-fide STAT5 binding site and miR-21 levels increased in HC11 mammary cells upon prolactin treatment. In vivo miR-21 was abundantly expressed in mammary epithelium at day 6 of pregnancy. Analysis of mice lacking miR-21 revealed that their mammary tissue developed normally during pregnancy and dams were able to nurse their pups. Our study demonstrated that although expression of miR-21 is under prolactin control through the transcription factors STAT5A/B its presence is dispensable for mammary development and lactation.
2014-01-01 | S-EPMC3907398 | BioStudies
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 | ArrayExpress
Project description:Development of T cells in the thymus is tightly controlled to continually produce functional, but not autoreactive, T cells. miRNAs provide a layer of post-transcriptional gene regulation to this process, but the role of many individual miRNAs in T-cell development remains unclear. miR-21 is prominently expressed in immature thymocytes followed by a steep decline in more mature cells. We hypothesized that such a dynamic expression was indicative of a regulatory function in intrathymic T-cell development. To test this hypothesis, we analyzed T-cell development in miR-21-deficient mice at steady state and under competitive conditions in mixed bone-marrow chimeras. We complemented analysis of knock-out animals by employing over-expression in vivo. Finally, we assessed miR-21 function in negative selection in vivo as well as differentiation in co-cultures. Together, these experiments revealed that miR-21 is largely dispensable for physiologic T-cell development. Given that miR-21 has been implicated in regulation of cellular stress responses, we assessed a potential role of miR-21 in endogenous regeneration of the thymus after sublethal irradiation. Again, miR-21 was completely dispensable in this process. We concluded that, despite prominent and highly dynamic expression in thymocytes, miR-21 expression was not required for physiologic T-cell development or endogenous regeneration.
2018-01-01 | S-EPMC6230590 | BioStudies
Project description:Study on the role of microRNAs (miRs) as regulators of gene expression through posttranscriptional gene silencing is currently gaining much interest,due to their wide involvement in different physiological processes. Understanding mammary gland development, lactation, and neoplasia in relation to miRs is essential. miR expression profiling of the mammary gland from different species in various developmental stages shows their role as critical regulators of development. miRs such as miR-126, miR-150, and miR-145 have been shown to be involved in lipid metabolism during lactation. In addition, lactogenic hormones influence miR expression as evidenced by overexpression of miR-148a in cow mammary epithelial cells, leading to enhanced lactation. Similarly, the miR-29 family modulates lactation-related gene expression by regulating DNA methylation of their promoters. Besides their role in development, lactation and involution, miRs are responsible for breast cancer development. Perturbed estrogen (E2) signaling is one of the major causes of breast cancer. Increased E2 levels cause altered expression of ER?, and ER?-miR cross-talk promotes tumour progression. miRs, such as miR-206, miR-34a, miR-17-5p, and miR-125 a/b are found to be tumour suppressors; whereas miR-21, miR-10B, and miR-155 are oncogenes. Oncogenic miRs like miR-21, miR-221, and miR-210 are overexpressed in triple negative breast cancer cases which can be diagnostic biomarker for this subtype of cancer. This review focuses on the recent findings concerning the role of miRs in developmental stages of the mammary gland (mainly lactation and involution stages) and their involvement in breast cancer progression. Further studies in this area will help us to understand the molecular details of mammary gland biology, as well as miRs that could be therapeutic targets of breast cancer.
| S-EPMC5609084 | BioStudies
Project description:Background: MicroRNAs (miRNAs) acting as negative regulators of gene expression are differentially expressed in intestinal tissues of patients with inflammatory bowel disease (IBD). Assessing the functional role of miRNAs in murine models of colitis facilitates elucidating the role of specific miRNAs in human IBD. The aim of this study was to determine the miRNA signature of murine models of colitis and to assess the influence of miR-21 on intestinal inflammation. Methods: miRNAs expression was accessed by microarray for acute and chronic murine model of colitis induced by DSS or TNBS. miR-21-deficient mouse and littermates controls were assessed in the standard DSS, TNBS and CD4+ T cell transfer models of colitis. RNAs of mouse colon and CD4+CD45RBHigh cells were analyzed by miRNA and mRNA microarray, and quantitative RT-PCR. Th1 polarization was accessed by flow-cytometry and ELISA. Results: Alterations of in miRNAs expression were identified for acute and chronic DSS colitis and TNBS colitis, receptively. The Expression of miRs-21, -142-3p and -223 was were distinct between DSS and TNBS models while overlap of numerous miRNAs was seen. Importantly, miRs-19b, -192 and -215, that are decreased in IBD, were significantly decreased in all 4 models of colitis. miR-21, which is increased in IBD, was increased in TNBS colitis but not the DSS colitis models. Further assessment of the miR-21-deficient 1-/- mice revealed that the deletion of miR-21 results in the exacerbation of both the TNBS and T cell-transfer models of colitis. Conclusions: miRNAs are differentially expressed in both human IBD and murine colitis, with overlap of several IBD-associated miRNAs. The demonstration that miR-21 deletion exacerbated CD4+ T cell-mediated models of colitis provides further evidence that miRNAs play significant roles in the pathogenesis of IBD. Gene expression profiles were established for normal miR-21-/- mice and wild type c57BL/6 mice (WT). Total of 6 samples with replicates were included in this study.
2014-07-23 | E-GEOD-59648 | ArrayExpress
Project description:Histone modifications have been implicated in stem cell maintenance and differentiation. We have analyzed genome-wide changes in gene expression and histone modifications during differentiation of multipotent human primary hematopoietic stem cells/progenitor cells (HSCs/HPCs) into erythrocyte precursors. Our data indicate that H3K4me1, H3K9me1, and H3K27me1 associate with enhancers of differentiation genes prior to their activation and correlate with basal expression, suggesting that these monomethylations are involved in the maintenance of activation potential required for differentiation. In addition, although the majority of genes associated with both H3K4me3 and H3K27me3 in HSCs/HPCs become silent and lose H3K4me3 after differentiation, those that lose H3K27me3 and become activated after differentiation are associated with increased levels of H2A.Z, H3K4me1, H3K9me1, H4K20me1, and RNA polymerase II in HSCs/HPCs. Thus, our data suggest that gene expression changes during differentiation are programmed by chromatin modifications present at the HSC/HPC stage and provide a resource for enhancer and promoter identification. Genome-wide analysis of 8 histone methylations, H2AZ, and RNA Polymerase II in human CD133+ and CD36+ cells. (20 samples in total) and global change in gene expression in human CD133+ and CD36+ cells. (4 samples in total)
2009-01-09 | E-GEOD-12646 | ArrayExpress
Project description:Fibrosis and cancer represent two major complications of chronic liver disease. MicroRNAs have been implicated in the development of fibrosis and cancer, thus constituting potential therapeutic targets. Here, we investigated the role of microRNA-21 (miR-21), a microRNA that has been implicated in the development of fibrosis in multiple organs and has also been suggested to act as an "oncomir." Accordingly, miR-21 was the microRNA that showed the strongest up-regulation in activated hepatic stellate cells (HSCs) in multiple models of fibrogenesis, with an 8-fold to 24-fold induction compared to quiescent HSCs. However, miR-21 antisense inhibition did not suppress the activation of murine or human HSCs in culture or in liver slices. Moreover, genetic deletion of miR-21 in two independently generated knockout mice or miR-21 antisense inhibition did not alter HSC activation or liver fibrosis in models of toxic and biliary liver injury. Despite a strong up-regulation of miR-21 in injury-associated hepatocellular carcinoma and in cholangiocarcinoma, miR-21 deletion or antisense inhibition did not reduce the development of liver tumors. As inhibition of the most up-regulated microRNA did not affect HSC activation, liver fibrosis, or fibrosis-associated liver cancer, we additionally tested the role of microRNAs in HSCs by HSC-specific Dicer deletion. Although Dicer deletion decreased microRNA expression in HSCs and altered the expression of select genes, it only exerted negligible effects on HSC activation and liver fibrosis. CONCLUSION:Genetic and pharmacologic manipulation of miR-21 does not inhibit the development of liver fibrosis and liver cancer. Moreover, suppression of microRNA synthesis does not significantly affect HSC phenotype and activation. (Hepatology 2018;67:2414-2429).
2018-01-01 | S-EPMC5930143 | BioStudies