title: Histone demethylases Kdm6ba and Kdm6bb redundantly promote cardiomyocyte proliferation during zebrafish heart ventricle maturation.
abstract: Trimethylation of lysine 27 on histone 3 (H3K27me3) by the Polycomb repressive complex 2 (PRC2) contributes to localized and inherited transcriptional repression. Kdm6b (Jmjd3) is a H3K27me3 demethylase that can relieve repression-associated H3K27me3 marks, thereby supporting activation of previously silenced genes. Kdm6b is proposed to contribute to early developmental cell fate specification, cardiovascular differentiation, and/or later steps of organogenesis, including endochondral bone formation and lung development. We pursued loss-of-function studies in zebrafish to define the conserved developmental roles of Kdm6b. kdm6ba and kdm6bb homozygous deficient zebrafish are each viable and fertile. However, loss of both kdm6ba and kdm6bb shows Kdm6b proteins share redundant and pleiotropic roles in organogenesis without impacting initial cell fate specification. In the developing heart, co-expressed Kdm6b proteins promote cardiomyocyte proliferation coupled with the initial stages of cardiac trabeculation. While newly formed trabecular cardiomyocytes display a striking transient decrease in bulk cellular H3K27me3 levels, this demethylation is independent of collective Kdm6b. Our results indicate a restricted and likely locus-specific role for Kdm6b demethylases during heart ventricle maturation rather than initial cardiogenesis.
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403-1229, United States; Department of Biology, University of Oregon, Eugene, OR 97403-1229, United States.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Akerberg
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403-1229, United States.
authors.forename: Astra
authors.initials: A
authors.lastname: Henner
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403-1229, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Stewart
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403-1229, United States; Department of Biology, University of Oregon, Eugene, OR 97403-1229, United States. Electronic address: kryn@uoregon.edu.
authors.forename: Kryn
authors.initials: K
authors.lastname: Stankunas
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006352:Heart Ventricles / Q000254:growth & development*; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D038081:Organogenesis / Q000235:genetics* / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D006657:Histones; D029961:Zebrafish Proteins; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C546330:kdm6bb protein, zebrafish; C000622648:lysine (K)-specific demethylase 6B, zebrafish
keywords: Cardiogenesis; H3K27me3; Histone demethylase; Kdm6b; Trabeculation; Ventricle