title: A Role for the Chromatin-Remodeling Factor BAZ1A in Neurodevelopment.
abstract: Chromatin-remodeling factors are required for a wide range of cellular and biological processes including development and cognition, mainly by regulating gene expression. As these functions would predict, deregulation of chromatin-remodeling factors causes various disease syndromes, including neurodevelopmental disorders. Recent reports have linked mutations in several genes coding for chromatin-remodeling factors to intellectual disability (ID). Here, we used exome sequencing and identified a nonsynonymous de novo mutation in BAZ1A (NM_182648.2:c.4043T > G, p.Phe1348Cys), encoding the ATP-utilizing chromatin assembly and remodeling factor 1 (ACF1), in a patient with unexplained ID. ACF1 has been previously reported to bind to the promoter of the vitamin D receptor (VDR)-regulated genes and suppress their expression. Our results show that the patient displays decreased binding of ACF1 to the promoter of the VDR-regulated gene CYP24A1. Using RNA sequencing, we find that the mutation affects the expression of genes involved in several pathways including vitamin D metabolism, Wnt signaling and synaptic formation. RNA sequencing of BAZ1A knockdown cells and Baz1a knockout mice revealed that BAZ1A carry out distinctive functions in different tissues. We also demonstrate that BAZ1A depletion influence the expression of genes important for nervous system development and function. Our data point to an important role for BAZ1A in neurodevelopment, and highlight a possible link for BAZ1A to ID.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Ammar
authors.initials: A
authors.lastname: Zaghlool
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Halvardson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Jin J
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Mitra
authors.initials: M
authors.lastname: Etemadikhah
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Antonia
authors.initials: A
authors.lastname: Kalushkova
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Konska
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Jernberg-Wiklund
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Thuresson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Feuk
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone; D059472:Exome; D053263:Gene Regulatory Networks; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D051379:Mice; D009420:Nervous System / Q000254:growth & development*; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D055366:Synaptic Potentials; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000092468:Bromodomain Containing Proteins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D018167:Receptors, Calcitriol; D014157:Transcription Factors; C492319:BAZ1A protein, human; D000092468:Bromodomain Containing Proteins; C579457:VDR protein, human
keywords: ACF1; BAZ1A; CYP24A1; Wnt signaling; epilepsy; intellectual disability; neurodevelopment; vitamin D metabolism