title: Nuclear factor erythroid-derived 2 (Nfe2) regulates JunD DNA-binding activity via acetylation: a novel mechanism regulating trophoblast differentiation.
abstract: We recently demonstrated that the bZip transcription factor nuclear factor erythroid-derived 2 (Nfe2) represses protein acetylation and expression of the transcription factor glial cell missing 1 (Gcm1) in trophoblast cells, preventing excess syncytiotrophoblast formation and permitting normal placental vascularization and embryonic growth. However, the Gcm1 promoter lacks a Nfe2-binding site and hence the mechanisms linking Nfe2 and Gcm1 expression remained unknown. Here we show that Nfe2 represses JunD DNA-binding activity to the Gcm1 promoter during syncytiotrophoblast differentiation. Interventional studies using knockdown and knockin approaches show that enhanced JunD DNA-binding activity is required for increased expression of Gcm1 and syncytiotrophoblast formation as well as impaired placental vascularization and reduced growth of Nfe2(-/-) embryos. Induction of Gcm1 expression requires binding of JunD to the -1441 site within the Gcm1 promoter, which is distinct from the -1314 site previously shown to induce Gcm1 expression by other bZip transcription factors. Nfe2 modulates JunD binding to the Gcm1 promoter via acetylation, as reducing JunD acetylation using the histone acetyltransferase inhibitor curcumin reverses the increased JunD DNA-binding activity observed in the absence of Nfe2. This identifies a novel mechanism through which bZip transcription factors interact. Within the placenta this interaction regulates Gcm1 expression, syncytiotrophoblast formation, placental vascularization, and embryonic growth.
authors.affiliation: Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, 69120 Heidelberg, Germany.
authors.forename: Muhammed
authors.initials: M
authors.lastname: Kashif
authors.forename: Andrea
authors.initials: A
authors.lastname: Hellwig
authors.forename: Said
authors.initials: S
authors.lastname: Hashemolhosseini
authors.forename: Varun
authors.initials: V
authors.lastname: Kumar
authors.forename: Fabian
authors.initials: F
authors.lastname: Bock
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.forename: Khurrum
authors.initials: K
authors.lastname: Shahzad
authors.forename: Satish
authors.initials: S
authors.lastname: Ranjan
authors.forename: Juliane
authors.initials: J
authors.lastname: Wolter
authors.forename: Thati
authors.initials: T
authors.lastname: Madhusudhan
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Peter
authors.initials: P
authors.lastname: Nawroth
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
mesh_terms: D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D009479:Neuropeptides / Q000235:genetics; D010920:Placenta / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C101631:Gcm1 protein, mouse; D050984:NF-E2 Transcription Factor, p45 Subunit; D009479:Neuropeptides; C494693:Nfe2 protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C528955:junD protein, mouse; D004247:DNA