Cell Stem Cell
Volume 8, Issue 5, 6 May 2011, Pages 525-537
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Article
MAP3K4/CBP-Regulated H2B Acetylation Controls Epithelial-Mesenchymal Transition in Trophoblast Stem Cells

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Summary

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.

Highlights

► TS cells lacking MAP3K4 activity (TSKI4) exhibit properties of stemness and EMT ► Loss of H2A/H2B acetylation by CBP induces EMT, but does not affect stemness ► TS cells maintain epithelial identity and stem cell renewal by independent mechanisms ► TSKI4 cells and human breast tumors share an intersecting EMT gene signature

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These authors contributed equally to this work