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Distinct STAT5 concentrations uniquely control establishment and differentiation of mammary epithelium during pregnancy

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Keunsoo Kang

PROVIDER: E-GEOD-37646 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration.

Yamaji Daisuke D Kang Keunsoo K Robinson Gertraud W GW Hennighausen Lothar L

Nucleic acids research 20121228 3

The transcription factors Signal Transducer and Activator of Transcription (STAT) 5A/B mediate prolactin-induced mammary development during pregnancy. However, it is not clear how the different processes, expansion and maturation of alveolar precursor cells and the differential induction of milk protein genes are regulated on a molecular level. We have used mouse genetics and genome-wide analyses to determine how altering concentrations of STAT5A and STAT5B impacts mammary epithelial development ...[more]

PMID: 23275557

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Loss of EZH2 results in precocious mammary gland development and the activation of STAT5-dependent genes

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

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Impact of STAT5 dosage and binding location on genetic and biological programs activated in mouse mammary epithelium during pregnancy.

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2012-09-18 | E-GEOD-40930 | biostudies-arrayexpress

Genome-wide binding of STAT3 and STAT5 under Th17 conditions (ChIP-Seq)

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2011-02-09 | E-GEOD-26552 | biostudies-arrayexpress

Loss of EZH2 results in enhanced recruitment of EZH1, Pol II and Stat5 and precocious mammary gland development

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 and accelerated activation of mammary signature genes. This coincided with enhanced occupancy by EZH1, Pol II and STAT5 to mammary-specific loci. 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. However, 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. ChIP-seq EZH1, EZH2, PolIII; WT and E2KO mammary cells

2015-01-27 | E-GEOD-65284 | biostudies-arrayexpress

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2011-04-24 | E-GEOD-27158 | biostudies-arrayexpress

Genome-wide analyses reveal the extent of opportunistic STAT5 binding that does not yield transcriptional activation of neighboring genes.

Project description:Signal Transducers and Activators of Transcription (STAT) 5A/B regulate cytokine-inducible genes upon binding to GAS motifs. It is not known what percentage of genes with GAS motifs bind to and are regulated by STAT5. Moreover, it is not clear whether genome-wide STAT5 binding is modulated by its concentration. To clarify these issues we established genome-wide STAT5 binding upon growth hormone (GH) stimulation of wild type mouse embryonic fibroblasts (MEFs) and MEFs overexpressing STAT5A more than 20-fold. Upon GH stimulation 23,827 and 111,939 STAT5A binding sites were detected in wild type and STAT5A overexpressing MEFs, respectively. 13,278 and 71,561 peaks contained at least one GAS motif. 1,586 and 8,613 binding sites were located within 2.5 kbp of promoter sequences, respectively. Stringent filtering revealed 78 genes in which the promoter/upstream region (-10kbp to +0.5kbp) was recognized by STAT5 both in wt and STAT5 overexpressing MEFs and 347 genes that bound STAT5 only in overexpressing cells. Genome-wide expression analyses identified that the majority of STAT5-bound genes was not under GH control. Up to 40% of STAT5-bound genes were not expressed. For the first time we demonstrate the magnitude of opportunistic genomic STAT5 binding that does not translate into transcriptional activation of neighboring genes. Genome-wide mapping of STAT5 binding in MEF cells (WT, KO; Stat5-/- and overexpression; STAT5A-Stat5-/-) upon growth hormone induction

2012-01-12 | E-GEOD-34986 | biostudies-arrayexpress

Prolactin-inducible Stat5a-mediated and Stat5b-mediated gene profiles

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2012-08-29 | E-GEOD-37781 | biostudies-arrayexpress

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