MAP3K4 Kinase Activity Controls Chromatin Remodelers for Transitions Between Epithelial and Mesenchymal Phenotypes in Trophoblast Stem Cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE92426 | GEO | 2017/03/07
SECONDARY ACCESSION(S): PRJNA357548
REPOSITORIES: GEO
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Project description:MAP3K4 is a serine/threonine kinase that regulates epithelial to mesenchymal transition (EMT). Trophoblast stem (TS) cells lacking MAP3K4 kinase activity (TSKI4 cells) are in an intermediate state of EMT, having reduced epithelial and increased mesenchymal marker expression. Reduced epithelial gene expression in TSKI4 cells was due to loss of H2BK5 promoter acetylation catalyzed by the histone acetyltransferase CBP. Herein, we show that MAP3K4 also regulates the ubiquitination and degradation of the deacetylase HDAC6. Due to the loss of MAP3K4 kinase activity, TSKI4 cells have elevated HDAC6 expression and activity. Knockdown of HDAC6 in TSKI4 cells restores epithelial features, defining HDAC6 as a key regulator of EMT controlled by MAP3K4. HDAC6 promotes EMT by directly deacetylating H2BK5 on promoters of tight junction genes claudin6 and occludin, inhibiting their expression. Thus, MAP3K4 is a master regulator that coordinates chromatin modifiers, CBP and HDAC6, to regulate the transition between epithelial and mesenchymal states.
2017-03-07 | GSE92425 | GEO
Project description:MAP3K4 is a serine/threonine kinase that regulates epithelial to mesenchymal transition (EMT). Trophoblast stem (TS) cells lacking MAP3K4 kinase activity (TSKI4 cells) are in an intermediate state of EMT, having reduced epithelial and increased mesenchymal marker expression. Reduced epithelial gene expression in TSKI4 cells was due to loss of H2BK5 promoter acetylation catalyzed by the histone acetyltransferase CBP. Herein, we show that MAP3K4 also regulates the ubiquitination and degradation of the deacetylase HDAC6. Due to the loss of MAP3K4 kinase activity, TSKI4 cells have elevated HDAC6 expression and activity. Knockdown of HDAC6 in TSKI4 cells restores epithelial features, defining HDAC6 as a key regulator of EMT controlled by MAP3K4. HDAC6 promotes EMT by directly deacetylating H2BK5 on promoters of tight junction genes claudin6 and occludin, inhibiting their expression. Thus, MAP3K4 is a master regulator that coordinates chromatin modifiers, CBP and HDAC6, to regulate the transition between epithelial and mesenchymal states.
2017-03-07 | GSE92394 | GEO
Project description:MAP3K4 Kinase Activity Controls Chromatin Remodelers for Transitions Between Epithelial and Mesenchymal Phenotypes in Trophoblast Stem Cells
| PRJNA357548 | ENA
Project description:Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT). Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histones H2A and H2B by CBP is required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties. The expression profile of MAP3K4-deficient TS cells defines an H2B acetylation-regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveals previously unrecognized genes potentially contributing to breast cancer.
| S-EPMC3091002 | biostudies-literature
Project description:The first epithelial-to-mesenchymal transition (EMT) occurs in trophoblast stem (TS) cells during implantation. Inactivation of the serine/threonine kinase MAP3K4 in TS cells (TSKI4 cells) induces an intermediate state of EMT, where cells retain stemness, lose epithelial markers, and gain mesenchymal characteristics. Investigation of relationships among MAP3K4 activity, stemness, and EMT in TS cells may reveal key regulators of EMT. Here, we show that MAP3K4 activity controls EMT through the ubiquitination and degradation of HDAC6. Loss of MAP3K4 activity in TSKI4 cells results in elevated HDAC6 expression and the deacetylation of cytoplasmic and nuclear targets. In the nucleus, HDAC6 deacetylates the promoters of tight junction genes, promoting the dissolution of tight junctions. Importantly, HDAC6 knockdown in TSKI4 cells restores epithelial features, including cell-cell adhesion and barrier formation. These data define a role for HDAC6 in regulating gene expression during transitions between epithelial and mesenchymal phenotypes.
| S-EPMC5496714 | biostudies-literature
Project description:Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT). Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histone H2B by CBP is specifically required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties. The expression profile of MAP3K4 deficient TS cells defines an H2B acetylation regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveal previously unrecognized genes potentially contributing to breast cancer. Three separate trophoblast stem (TS) cell conditions were compared to define the gene expression changes that occur with the induction of epithelial-mesenchymal transition (EMT) in TS cells. These conditions were TS cells differentiated for 4 days (T^Diff), TS cells differentiated for 4-days and isolated following invasion through Matrigel (T^Inv), and TS cells with an inactive MAP3K4 (TS^KI4). All conditions were normalized to wild-type control TS cells (TS^WT). T^Diff and T^Inv were analyzed in triplicate. TS^KI4 was analyzed in duplicate in two independent biological replicates.
2011-05-27 | E-GEOD-27883 | biostudies-arrayexpress
Project description:Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT). Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histone H2B by CBP is specifically required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties. The expression profile of MAP3K4 deficient TS cells defines an H2B acetylation regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveal previously unrecognized genes potentially contributing to breast cancer.
2011-05-27 | GSE27883 | GEO
Project description:Sex determination requires the commitment of bipotential gonads to either a testis or an ovarian fate. Gene deletion of the kinase Map3k4 results in gonadal sex reversal in XY mice, and transgenic re-expression of Map3k4 rescues the sex reversal phenotype. Map3k4 encodes a large, multi-functional protein possessing a kinase domain and several, additional protein-protein interaction domains. Although MAP3K4 plays a critical role in male gonadal sex determination, it is unknown if the kinase activity of MAP3K4 is required. Here, we use mice expressing full-length, kinase-inactive MAP3K4 from the endogenous Map3k4 locus to examine the requirement of MAP3K4 kinase activity in sex determination. Although homozygous kinase-inactivation of MAP3K4 (Map3k4KI/KI) is lethal, a small fraction survive to adulthood. We show Map3k4KI/KI adults exhibit a 4:1 female-biased sex ratio. Many adult Map3k4KI/KI phenotypic females have a Y chromosome. XY Map3k4KI/KI adults with sex reversal display female mating behavior, but do not give rise to offspring. Reproductive organs are overtly female, but there is a broad spectrum of ovarian phenotypes, including ovarian absence, primitive ovaries, reduced ovarian size, and ovaries having follicles in all stages of development. Further, XY Map3k4KI/KI adults are smaller than either male or female Map3k4WT/WT mice. Examination of the critical stage of gonadal sex determination at E11.5 shows that loss of MAP3K4 kinase activity results in the loss of Sry expression in XY Map3k4KI/KI embryos, indicating embryonic male gonadal sex reversal. Together, these findings demonstrate the essential role for kinase activity of MAP3K4 in male gonadal sex determination.
| S-EPMC8660160 | biostudies-literature
Project description:Coordinated gene expression is required for phenotypic switching between epithelial and mesenchymal phenotypes during normal development and in disease states. Trophoblast stem (TS) cells undergo epithelial-mesenchymal transition (EMT) during implantation and placentation. Mechanisms coordinating gene expression during these processes are poorly understood. We have previously demonstrated that MAP3K4-regulated chromatin modifiers CBP and HDAC6 each regulate thousands of genes during EMT in TS cells. Here we show that CBP and HDAC6 coordinate expression of only 183 genes predicted to be critical regulators of phenotypic switching. The highest-ranking co-regulated gene is the NF-κB family member Rel. Although NF-κB is primarily regulated post-transcriptionally, CBP and HDAC6 control Rel transcript levels by binding Rel regulatory regions and controlling histone acetylation. REL re-expression in mesenchymal-like TS cells induces a mesenchymal-epithelial transition. Importantly, REL forms a feedback loop, blocking HDAC6 expression and nuclear localization. Together, our work defines a developmental program coordinating phenotypic switching.
| S-EPMC7455715 | biostudies-literature
Project description:To support tissue and organ development, cells transition between epithelial and mesenchymal states. Here, we have investigated how mesoderm cells change state in Drosophila embryos and whether fibroblast growth factor (FGF) signaling plays a role. During gastrulation, presumptive mesoderm cells invaginate, undergo an epithelial-to-mesenchymal state transition (EMT) and migrate upon the ectoderm. Our data show that EMT is a prolonged process in which adherens junctions progressively decrease in number throughout the migration of mesoderm cells. FGF influences adherens junction number and promotes mesoderm cell division, which we propose decreases cell-cell attachments to support slow EMT while retaining collective cell movement. We also found that, at the completion of migration, cells form a monolayer and undergo a reverse mesenchymal-to-epithelial transition (MET). FGF activity leads to accumulation of β-integrin Myospheroid basally and cell polarity factor Bazooka apically within mesoderm cells, thereby reestablishing apicobasal cell polarity in an epithelialized state in which cells express both E-Cadherin and N-Cadherin. In summary, FGF plays a dynamic role in supporting mesoderm cell development to ensure collective mesoderm cell movements, as well as proper differentiation of mesoderm cell types.
| S-EPMC6198468 | biostudies-literature