title: MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition.
abstract: 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 (TSKI4cells) 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 TSKI4cells 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 TSKI4cells 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.
authors.affiliation: Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mobley
authors.affiliation: Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Raghu
authors.affiliation: Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA.
authors.forename: Lauren D
authors.initials: LD
authors.lastname: Duke
authors.affiliation: Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA.
authors.forename: Kayley
authors.initials: K
authors.lastname: Abell-Hart
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Jon S
authors.initials: JS
authors.lastname: Zawistowski
authors.affiliation: Department of Biomedical Engineering and Curriculum in Bioinformatics and Computational Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Kyla
authors.initials: K
authors.lastname: Lutz
authors.affiliation: Department of Biomedical Engineering and Curriculum in Bioinformatics and Computational Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Gomez
authors.affiliation: Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA.
authors.forename: Sujoy
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA.
authors.forename: Ramin
authors.initials: R
authors.lastname: Homayouni
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
authors.affiliation: Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA; Department of Biomedical Engineering, University of Memphis, Memphis, TN 38152, USA. Electronic address: anabell@memphis.edu.
authors.forename: Amy N
authors.initials: AN
authors.lastname: Abell
mesh_terms: D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D000073864:Histone Deacetylase 6 / Q000378:metabolism*; D048768:MAP Kinase Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D059748:Proteolysis; D013234:Stem Cells / Q000166:cytology*; D062725:Tight Junction Proteins / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002843:Chromatin; D062725:Tight Junction Proteins; D048768:MAP Kinase Kinase Kinase 4; C482780:Map3k4 protein, mouse; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6
keywords: HDAC6; MAP3K4; chromatin remodelers; development; epigenetics; epithelial to mesenchymal transition; histone acetylation; histone deacetylase; tight junctions; trophoblast stem cells