title: The histone demethylase Kdm3a is essential to progression through differentiation.
abstract: Histone demethylation has important roles in regulating gene expression and forms part of the epigenetic memory system that regulates cell fate and identity by still poorly understood mechanisms. Here, we examined the role of histone demethylase Kdm3a during cell differentiation, showing that Kdm3a is essential for differentiation into parietal endoderm-like (PE) cells in the F9 mouse embryonal carcinoma model. We identified a number of target genes regulated by Kdm3a during endoderm differentiation; among the most dysregulated were the three developmental master regulators Dab2, Pdlim4 and FoxQ1. We show that dysregulation of the expression of these genes correlates with Kdm3a H3K9me2 demethylase activity. We further demonstrate that either Dab2 depletion or Kdm3a depletion prevents F9 cells from fully differentiating into PE cells, but that ectopic expression of Dab2 cannot compensate for Kdm3a knockdown; Dab2 is thus necessary, but insufficient on its own, to promote complete terminal differentiation. We conclude that Kdm3a plays a crucial role in progression through PE differentiation by regulating expression of a set of endoderm differentiation master genes. The emergence of Kdm3a as a key modulator of cell fate decision strengthens the view that histone demethylases are essential to cell differentiation.
authors.affiliation: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
authors.forename: Marielle
authors.initials: M
authors.lastname: Herzog
authors.forename: Eléonore
authors.initials: E
authors.lastname: Josseaux
authors.forename: Sarah
authors.initials: S
authors.lastname: Dedeurwaerder
authors.forename: Emilie
authors.initials: E
authors.lastname: Calonne
authors.forename: Michael
authors.initials: M
authors.lastname: Volkmar
authors.forename: François
authors.initials: F
authors.lastname: Fuks
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002454:Cell Differentiation / Q000235:genetics*; D054278:Embryonal Carcinoma Stem Cells; D004707:Endoderm / Q000166:cytology; D051858:Forkhead Transcription Factors / Q000235:genetics; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D060588:LIM Domain Proteins / Q000235:genetics; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics; D034622:RNA Interference
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; C478773:Dab2 protein, mouse; D051858:Forkhead Transcription Factors; C107579:Foxq1 protein, mouse; D006657:Histones; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; C486248:Pdlim4 protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; C511045:Kdm3a protein, mouse