Similar Datasets
Project description:We demonstrate that loss of the histone H3K9 methyltransferase G9a in the developing mammary epithelium results in de novo chromatin opening which leads to severely impaired development of the mammary ductal tree, concomitant with impaired stem cell potential and disrupted intraductal polarity. Intriguingly, these phenotypes are not attributed to alterations in lineage specification and fidelity of the basal and luminal cell fates. Instead, increased chromatin opening in G9a-ablated mammary epithelium results in derepression of Long Terminal Repeat (LTR) sequences, most prominently of the ERVK family. When reverse-transcribed, these endogenous retroviruses generate double-stranded DNA (dsDNA) that accumulates in the cytosol of G9acKO mammary epithelial cells and trigger a pyroptotic antiviral innate immune response within mammary fat pads. Importantly, this altered G9acKO mammary milieu precludes functional outgrowth of even wild-type mammary stem cells upon transplantation. Our results show that tight repression of endogenous retroviruses is required for proper mammary gland development and maintenance. We demonstrate that altering chromatin accessibility of retroviral elements, as occurs during aging and cancer, severely disrupts functional mammary gland development and mammary stem cell activity through both cell autonomous and cell non-autonomous mechanisms.
2021-05-18 | GSE168624 | GEO
Project description:We demonstrate that loss of the histone H3K9 methyltransferase G9a in the developing mammary epithelium results in de novo chromatin opening which leads to severely impaired development of the mammary ductal tree, concomitant with impaired stem cell potential and disrupted intraductal polarity. Intriguingly, these phenotypes are not attributed to alterations in lineage specification and fidelity of the basal and luminal cell fates. Instead, increased chromatin opening in G9a-ablated mammary epithelium results in derepression of Long Terminal Repeat (LTR) sequences, most prominently of the ERVK family. When reverse-transcribed, these endogenous retroviruses generate double-stranded DNA (dsDNA) that accumulates in the cytosol of G9acKO mammary epithelial cells and trigger a pyroptotic antiviral innate immune response within mammary fat pads. Importantly, this altered G9acKO mammary milieu precludes functional outgrowth of even wild-type mammary stem cells upon transplantation. Our results show that tight repression of endogenous retroviruses is required for proper mammary gland development and maintenance. We demonstrate that altering chromatin accessibility of retroviral elements, as occurs during aging and cancer, severely disrupts functional mammary gland development and mammary stem cell activity through both cell autonomous and cell non-autonomous mechanisms.
2021-05-18 | GSE149953 | GEO
Project description:We demonstrate that loss of the histone H3K9 methyltransferase G9a in the developing mammary epithelium results in de novo chromatin opening which leads to severely impaired development of the mammary ductal tree, concomitant with impaired stem cell potential and disrupted intraductal polarity. Intriguingly, these phenotypes are not attributed to alterations in lineage specification and fidelity of the basal and luminal cell fates. Instead, increased chromatin opening in G9a-ablated mammary epithelium results in derepression of Long Terminal Repeat (LTR) sequences, most prominently of the ERVK family. When reverse-transcribed, these endogenous retroviruses generate double-stranded DNA (dsDNA) that accumulates in the cytosol of G9acKO mammary epithelial cells and trigger a pyroptotic antiviral innate immune response within mammary fat pads. Importantly, this altered G9acKO mammary milieu precludes functional outgrowth of even wild-type mammary stem cells upon transplantation. Our results show that tight repression of endogenous retroviruses is required for proper mammary gland development and maintenance. We demonstrate that altering chromatin accessibility of retroviral elements, as occurs during aging and cancer, severely disrupts functional mammary gland development and mammary stem cell activity through both cell autonomous and cell non-autonomous mechanisms.
2021-05-18 | GSE149977 | GEO
Project description:We demonstrate that loss of the histone H3K9 methyltransferase G9a in the developing mammary epithelium results in de novo chromatin opening which leads to severely impaired development of the mammary ductal tree, concomitant with impaired stem cell potential and disrupted intraductal polarity. Intriguingly, these phenotypes are not attributed to alterations in lineage specification and fidelity of the basal and luminal cell fates. Instead, increased chromatin opening in G9a-ablated mammary epithelium results in derepression of Long Terminal Repeat (LTR) sequences, most prominently of the ERVK family. When reverse-transcribed, these endogenous retroviruses generate double-stranded DNA (dsDNA) that accumulates in the cytosol of G9acKO mammary epithelial cells and trigger a pyroptotic antiviral innate immune response within mammary fat pads. Importantly, this altered G9acKO mammary milieu precludes functional outgrowth of even wild-type mammary stem cells upon transplantation. Our results show that tight repression of endogenous retroviruses is required for proper mammary gland development and maintenance. We demonstrate that altering chromatin accessibility of retroviral elements, as occurs during aging and cancer, severely disrupts functional mammary gland development and mammary stem cell activity through both cell autonomous and cell non-autonomous mechanisms.
2021-05-18 | GSE149976 | GEO
Project description:Repression of endogenous retroviruses is required for mammary gland development and homeostasis
| PRJNA630715 | ENA
Project description:Repression of endogenous retroviruses is required for mammary gland development and homeostasis [microarray]
| PRJNA713294 | ENA
Project description:Repression of endogenous retroviruses is required for mammary gland development and homeostasis [RNA-Seq]
| PRJNA630719 | ENA
Project description:Repression of endogenous retroviruses is required for mammary gland development and homeostasis [ATAC-Seq]
| PRJNA630717 | ENA
Project description:Repression of endogenous retroviruses is required for mammary gland development and homeostasis [scRNA-Seq]
| PRJNA630720 | ENA
Project description:P190A and p190B Rho GTPase activating proteins (GAPs) are essential genes that have distinct, but overlapping roles in the developing nervous system. Previous studies from our laboratory demonstrated that p190B is required for mammary gland morphogenesis, and we hypothesized that p190A might have a distinct role in the developing mammary gland. To test this hypothesis, we examined mammary gland development in p190A-deficient mice. P190A expression was detected by in situ hybridization in the developing E14.5day embryonic mammary bud and within the ducts, terminal end buds (TEBs), and surrounding stroma of the developing virgin mammary gland. In contrast to previous results with p190B, examination of p190A heterozygous mammary glands demonstrated that p190A deficiency disrupted TEB morphology, but did not significantly delay ductal outgrowth indicating haploinsufficiency for TEB development. To examine the effects of homozygous deletion of p190A, embryonic mammary buds were rescued by transplantation into the cleared fat pads of SCID/Beige mice. Complete loss of p190A function inhibited ductal outgrowth in comparison to wildtype transplants (51% vs. 94% fat pad filled). In addition, the transplantation take rate of p190A deficient whole gland transplants from E18.5 embryos was significantly reduced compared to wildtype transplants (31% vs. 90%, respectively). These results suggest that p190A function in both the epithelium and stroma is required for mammary gland development. Immunostaining for p63 demonstrated that the myoepithelial cell layer is disrupted in the p190A deficient glands, which may result from the defective cell adhesion between the cap and body cell layers detected in the TEBs. The number of estrogen- and progesterone receptor-positive cells, as well as the expression levels of these receptors was increased in p190A deficient outgrowths. These data suggest that p190A is required in both the epithelial and stromal compartments for ductal outgrowth and that it may play a role in mammary epithelial cell differentiation.
| S-EPMC3215776 | biostudies-literature