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A MYC-driven change in mitochondrial dynamics limits stem cell properties of mammary epithelial cells (RNA-seq)

ABSTRACT: In several developmental lineages, an increase in expression of the MYC proto-oncogene drives the transition from quiescent stem cells to transit amplifying cells. The mechanism by which MYC restricts self-renewal of adult stem cells is unknown. Here, we show that MYC activates a stereotypic transcriptional program of genes involved in protein translation and mitochondrial biogenesis in mammary epithelial cells and indirectly inhibits the YAP/TAZ co-activators that are essential for mammary stem cell self-renewal. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. PLD6 mediates a change in the mitochondrial fusion/fission balance that promotes nuclear export of YAP/TAZ in a LATS- and RHO-independent manner. Mouse models and human pathological data confirm that MYC suppresses YAP/TAZ activity in mammary tumors. PLD6 is also required for glutaminolysis, arguing that MYC-dependent changes in mitochondrial dynamics balance cellular energy metabolism with the self-renewal potential of adult stem cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66250 | GEO | 2015/10/28

SECONDARY ACCESSION(S): PRJNA276279

REPOSITORIES: GEO

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A MYC-driven change in mitochondrial dynamics limits stem cell properties of mammary epithelial cells (ChIP-seq)

Project description:In several developmental lineages, an increase in expression of the MYC proto-oncogene drives the transition from quiescent stem cells to transit amplifying cells. The mechanism by which MYC restricts self-renewal of adult stem cells is unknown. Here, we show that MYC activates a stereotypic transcriptional program of genes involved in protein translation and mitochondrial biogenesis in mammary epithelial cells and indirectly inhibits the YAP/TAZ co-activators that are essential for mammary stem cell self-renewal. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. PLD6 mediates a change in the mitochondrial fusion/fission balance that promotes nuclear export of YAP/TAZ in a LATS- and RHO-independent manner. Mouse models and human pathological data confirm that MYC suppresses YAP/TAZ activity in mammary tumors. PLD6 is also required for glutaminolysis, arguing that MYC-dependent changes in mitochondrial dynamics balance cellular energy metabolism with the self-renewal potential of adult stem cells. ChIP-Seq experiments for MYC-HA (HA-IP) performed in IMEC primary breast epithelial cells. Input-samples were sequenced as controlls.

2015-10-28 | E-GEOD-66252 | biostudies-arrayexpress

A MYC-driven change in mitochondrial dynamics limits stem cell properties of mammary epithelial cells (RNA-seq)

Project description:In several developmental lineages, an increase in expression of the MYC proto-oncogene drives the transition from quiescent stem cells to transit amplifying cells. The mechanism by which MYC restricts self-renewal of adult stem cells is unknown. Here, we show that MYC activates a stereotypic transcriptional program of genes involved in protein translation and mitochondrial biogenesis in mammary epithelial cells and indirectly inhibits the YAP/TAZ co-activators that are essential for mammary stem cell self-renewal. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. PLD6 mediates a change in the mitochondrial fusion/fission balance that promotes nuclear export of YAP/TAZ in a LATS- and RHO-independent manner. Mouse models and human pathological data confirm that MYC suppresses YAP/TAZ activity in mammary tumors. PLD6 is also required for glutaminolysis, arguing that MYC-dependent changes in mitochondrial dynamics balance cellular energy metabolism with the self-renewal potential of adult stem cells. RNA-Seq Experiments in 2 different primary breast epithelial cell lines (HMLE, which were sorted according to CD44/CD24 surface markers & unsorted IMEC). Both cell lines expressed a doxycycline-inducible version of MYC. For the HMLE cell line DGE analysis was performed for the uninduced (EtOH) situation, comparing CD44high vs CD44 low and for the induced situation Dox vs. EtOH for the CD44high population. For the IMEC cell line DGE was performed by comparing Dox-treated populations expressing either Dox-inducible MYC or a vector control which allows to filter out potential effects due to doxycycline treatment.

2015-10-28 | E-GEOD-66250 | biostudies-arrayexpress

A MYC-driven change in mitochondrial dynamics limits stem cell properties of mammary epithelial cells (ChIP-seq)

2015-10-28 | GSE66252 | GEO

Regulation of muscle stem cell function by Mpp7, Amot, Yap and Taz

Project description:Coordinating mechanical sensing and transcription activation is essential for muscle stem cell (MuSC) function during muscle regeneration. Here we report that MPP7, localized at the apical side of quiescent MuSCs, is an important regulator in MuSC activation, including proliferation and self-renewal. Mechanistically, MPP7 translocates to cell nucleus in response to the change of actin polymerization state with its binding partner AMOT (an actin binding protein) upon MuSC activation and acts to enhance the transcription activity of YAP and TAZ in the MuSC. RNA-seq of MuSCs isolated from control (Con), Mpp7 conditional knockout (cKO), Amot cKO, and Yap and Taz double cKO (YapTaz cKO) after 48 hrs in culture (for activation) in 2 replicas was used to determine the downtream genes regulated by Mpp7, Amot, Yap and Taz. Carm1 was one of the commonly shared down-regulated genes in all 3 cKOs and has been shown to be critical for MuSC self-renewal. We further demonstrated that the MPP7-PDZ domain interacts with TAZ indirectly via AMOT, and the MPP7-L27 domain cooperates with TAZ and another trsncription factor YY1 to regulate a select set of donwstream genes, including Carm1, for MuSC proliferation and self-renewal. Our data identified a coordinated molecular network from mechanical sensing to transcription regulation for MuSC function during muscle regeneration.

2023-10-07 | GSE241340 | GEO

De novo generation of somatic stem cells from differentiated cells [mammary]

Project description:To investigate the role of YAP/TAZ as factors able to convert differentiated cells into stem cells of the same tissue, we compared the expression profiles of mammary organoids (yOrg) obtained by doxycycline-inducible expression of YAP in luminal differentiated mammary cells with original luminal differentiated mammary cells (Lum) and organoids from native mammary stem cells (Org).

2016-09-10 | GSE70164 | GEO

Microarray of MCF10A cells with/without LATS1/2, expressing YAP/TAZ or ESR1 cDNA

Project description:Cell fate perturbations underlie many human diseases, including breast cancer. However, the regulation of breast cell fate remains largely elusive. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors. Breast cancer originates from this epithelium but the molecular mechanisms underlying breast epithelial hierarchy remain ill-defined. Mouse and human luminal cells express keratins (K)18, 8, 19 and/or estrogen receptor α (ERα) and progesterone receptor (PR), their basal counterparts express K5, 14 and/or p63 and/or α-smooth-muscle actin (α-SMA)4-6. In this study, using a high-content confocal image-based shRNA screen for tumor suppressors regulating human breast cell fate, we discovered that ablation of the Hippo kinases large tumor suppressor (LATS) 1 and 2, promoted luminal fate and increased the number of bipotent and luminal progenitors, the proposed cell-of-origin of most human breast cancers. Mechanistically, we discovered a crosstalk between Hippo and ERα signaling. In the presence of LATS, ERα was targeted for ubiquitination and proteasomal degradation. Loss of LATS stabilized ERα and Hippo effectors YAP/TAZ, which in concert control breast cell fate via intrinsic and paracrine mechanisms. Our findings uncover a novel non-canonical (i.e., YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate. In this dataset, we provide microarray gene expression analysis of normal breast epithelial cells, freshly dissociated from reduction mammoplasties, in which LATS1/2 were knocked down comparing it to non-targeting control expressing breast cells.

2017-01-27 | GSE80055 | GEO

miR205 Regulates Mammary Gland Development and Stem Cell Self-renewal through YAP and Wnt signaling

Project description:Mammary gland development is fueled by stem cell self-renewal and differentiation. External cues from the microenvironment coupled with internal cues such as post-transcriptional regulation exerted by miRNAs regulate stem cell behavior and stem cell fate. We have identified a miR205 regulatory network required for mammary gland morphogenesis and stem cell maintenance. In the postnatal mammary gland, miR205 is predominantly expressed in the basal/stem cell enriched population. Conditional deletion of miR205 in mammary epithelial cells severely impaired stem cell self-renewal and mammary repopulating potential both in vitro and in vivo. miR205 null glands displayed significant changes in the basal population, basement membrane and stroma. NKD1 and PP2A-B56, which inhibit the Wnt signaling pathway, and AMOT, which causes YAP cytoplasmic retention and inactivation were identified as miR205 downstream effectors. Collectively these findings reveal an essential role of miR205 in mammary gland development.

2018-12-27 | GSE124364 | GEO

Muscle stems cell LC-MS - Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function

Project description:Abstract Hippo pathway downstream effectors Yap and Taz play key roles in cell proliferation and regeneration, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed Taz in vivo and ex vivo in comparison to Yap. Taz was expressed in activated satellite cells. siRNA knockdown or constitutive expression of wildtype or constitutively active TAZ mutants showed that TAZ promoted proliferation, a function that was shared with YAP. However, at later stages of myogenesis, TAZ also enhanced myogenic differentiation of myoblasts, whereas YAP inhibits such differentiation. Functionally, while muscle growth was mildly affected in Taz (gene symbol Wwtr1-/-) knockout mice, there were no overt effect on regeneration. However, conditional knockout of Yap in satellite cells of Pax7Cre-ERT2/+ : Yapflox/flox : Rosa26Lacz mice produced a marked regeneration deficit. To identify potential mechanisms, microarray analysis showed many common Taz/Yap targets, but Taz also regulates some genes independently of Yap, including myogenic genes such as Pax7, Myf5 and Myod1. Proteomic analysis of Yap/Taz revealed many common binding partners, but Taz also interacts with proteins distinct from Yap, that are mainly involved in myogenesis and aspects of cytoskeleton organization. Neither TAZ nor YAP bind members of the Wnt destruction complex but both extensively changed expression of Wnt and Wnt-cross talking genes with known roles in myogenesis. Finally, TAZ operates through Tead4 to enhance myogenic differentiation. In summary, Taz and Yap have overlapping functions in promoting myoblast proliferation but Taz then switches to promote myogenic differentiation.

2017-06-13 | PXD005751 | Pride

DUB1 suppresses Hippo signaling via modulating TAZ protein in gastric cancer

Project description:The Hippo pathway functions as a tumor-suppressor pathway in human cancers, while the dys-function of Hippo pathway is frequently observed in malignancies. Although the YAP/TAZ activity is tightly controlled by the phosphorylation cascade of MST-LATS-YAP/TAZ axis, it is still unclear why YAP/TAZ protein is activated in human cancers, even Hippo pathway is still active. Besides phosphorylation, recent studies implicate that several post-translational modifications also play critical roles in modulating TAZ function, including ubiquitination. Here, by a DUB (Deubiquitinases) siRNA screening library, we discovered DUB1 as a critical modulator to facilitate gastric cancer stemness and progression, which deubiquitinated and activated TAZ protein. We also identified DUB1 was elevated in gastric cancer, which correlated with TAZ activation and poor survival. DUB1 associated with TAZ protein and deubiquitinated TAZ at several lysine sites, which subsequently stabilized and facilitated TAZ function. Our study revealed a novel deubiquitinase of Hippo/TAZ axis and one possible therapeutic target for Hippo-driven gastric cancer.

2022-02-12 | GSE196262 | GEO

Transcriptional co-activators YAP1-TAZ of Hippo signalling in doxorubicin-induced cardiomyopathy

Project description:Aims: Hippo signalling is an evolutionarily conserved pathway that controls organ size by regulating apoptosis, cell proliferation and stem cell self-renewal. Recently, the pathway has been shown to exert powerful growth regulatory activity in cardiomyocytes. However, the functional role of this stress- and cell death-related pathway in the human heart and cardiomyocytes is not known. In this study, we investigated the role of the transcriptional co-activators of Hippo signalling, YAP and TAZ, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in response to cardiotoxic agents and investigated the effects of modulating the pathway on cardiomyocyte function and survival. Methods and Results: RNA sequencing analysis of human heart samples with doxorubicin-induced end-stage heart failure and healthy controls showed YAP and ERBB2 (HER2) as upstream regulators of differentially expressed genes correlated with doxorubicin treatment. Thus, we tested the effects of doxorubicin and/or small molecule inhibitor lapatinib on hiPSC-CM in vitro . Using an automated high contentscreen of 96 clinically relevant chemotherapeutic drugs, we showed that doxorubicin induced the highest activation of YAP/TAZ nuclear translocation in both hiPSC-CM and control MCF7 breast cancer cells. The overexpression of YAP rescued doxorubicin- induced cell loss in hiPSC-CM by inhibiting apoptosis and inducing proliferation. In contrast, silencing of YAP and TAZ by siRNAs resulted in elevated mitochondrial membrane potential loss in response to doxorubicin. Human iPSC-CM calcium transients did not change in response to YAP/TAZ silencing. Conclusions: Our results suggest that Hippo signalling is involved in clinical anthracycline-induced cardiomyopathy. Modelling with hiPSC-CM in vitro showed similar responses to doxorubicin as adult cardiomyocytes and revealed a potential cardioprotective effect of YAP in doxorubicin-induced cardiotoxicity.

2022-01-21 | GSE193861 | GEO

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