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MAP3K4 Kinase Activity Controls Chromatin Remodelers for Transitions Between Epithelial and Mesenchymal Phenotypes in Trophoblast Stem Cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE92426 | GEO | 2017/03/07

SECONDARY ACCESSION(S): PRJNA357548

REPOSITORIES: GEO

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MAP3K4 Kinase Activity Controls Chromatin Remodelers for Transitions Between Epithelial and Mesenchymal Phenotypes in Trophoblast Stem Cells [ChIP-Seq]

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.

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MAP3K4 Kinase Activity Controls Chromatin Remodelers for Transitions Between Epithelial and Mesenchymal Phenotypes in Trophoblast Stem Cells [RNA-Seq]

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MAP3K4 Kinase Activity Controls Chromatin Remodelers for Transitions Between Epithelial and Mesenchymal Phenotypes in Trophoblast Stem Cells

Project description:MAP3K4 Kinase Activity Controls Chromatin Remodelers for Transitions Between Epithelial and Mesenchymal Phenotypes in Trophoblast Stem Cells

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MAP3K4/CBP-regulated H2B acetylation controls epithelial-mesenchymal transition in trophoblast stem cells.

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MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition.

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MAP3K4/CBP Regulated H2B acetylation Controls Epithelial-Mesenchymal Transition in Trophoblast Stem Cells

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.

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MAP3K4/CBP Regulated H2B acetylation Controls Epithelial-Mesenchymal Transition in Trophoblast Stem Cells

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Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching.

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