title: Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.
abstract: Epigenetic mechanisms are important in different neurological disorders, and one such mechanism is histone acetylation. The multivalent chromatin regulator BRPF1 (bromodomain- and plant homeodomain-linked (PHD) zinc finger-containing protein 1) recognizes different epigenetic marks and activates three histone acetyltransferases, so it is both a reader and a co-writer of the epigenetic language. The three histone acetyltransferases are MOZ, MORF, and HBO1, which are also known as lysine acetyltransferase 6A (KAT6A), KAT6B, and KAT7, respectively. The MORF gene is mutated in four neurodevelopmental disorders sharing the characteristic of intellectual disability and frequently displaying callosal agenesis. Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis. With respect to the control, the mutant forebrain contained fewer Tbr2-positive intermediate neuronal progenitors and displayed aberrant neurogenesis. Molecularly, Brpf1 loss led to decreased transcription of multiple genes, such as Robo3 and Otx1, important for neocortical development. Surprisingly, elevated expression of different Hox genes and various other transcription factors, such as Lhx4, Foxa1, Tbx5, and Twist1, was also observed. These results thus identify an important role of Brpf1 in regulating forebrain development and suggest that it acts as both an activator and a silencer of gene expression in vivo.
authors.affiliation: From the Rosalind & Morris Goodman Cancer Research Center, Department of Medicine, McGill University, Quebec H3A 1A3.
authors.forename: Linya
authors.initials: L
authors.lastname: You
authors.affiliation: the National Research Council Canada, Montreal, Quebec H4P 2R2, and.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Zou
authors.affiliation: From the Rosalind & Morris Goodman Cancer Research Center.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: From the Rosalind & Morris Goodman Cancer Research Center.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Bertos
authors.affiliation: From the Rosalind & Morris Goodman Cancer Research Center, Department of Medicine, McGill University, Quebec H3A 1A3, the Department of Biochemistry, McGill University and McGill University Health Center, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.affiliation: the National Research Council Canada, Montreal, Quebec H4P 2R2, and.
authors.forename: Edwin
authors.initials: E
authors.lastname: Wang
authors.affiliation: From the Rosalind & Morris Goodman Cancer Research Center, Department of Medicine, McGill University, Quebec H3A 1A3, the Department of Biochemistry, McGill University and McGill University Health Center, Montreal, Quebec H3A 1A3, Canada xiang-jiao.yang@mcgill.ca.
authors.forename: Xiang-Jiao
authors.initials: XJ
authors.lastname: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D061085:Agenesis of Corpus Callosum / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000002:abnormalities* / Q000254:growth & development* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003337:Corpus Callosum / Q000254:growth & development / Q000378:metabolism; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis; D015533:Transcriptional Activation; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C000597967:BRPF1 protein, mouse; D000092468:Bromodomain Containing Proteins
keywords: BRPF1; Brain Development; Bromodomain; Chromatin Modification; Gene Regulation; Histone Acetylase; Histone Acetyltransferase; Microarray; Pleckstrin Homology Domain Finger