title: The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors.
abstract: Lysine acetylation has recently emerged as an important post-translational modification in diverse organisms, but relatively little is known about its roles in mammalian development and stem cells. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively. While the MOZ and MORF genes are rearranged in leukemia, the MORF gene is also mutated in prostate and other cancers and in four genetic disorders with intellectual disability. Here we show that forebrain-specific inactivation of the mouse Brpf1 gene causes hypoplasia in the dentate gyrus, including underdevelopment of the suprapyramidal blade and complete loss of the infrapyramidal blade. We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors. We further demonstrate that Brpf1 loss deregulates neuronal migration, cell cycle progression and transcriptional control, thereby causing abnormal morphogenesis of the hippocampus. These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.
authors.affiliation: The Rosalind & Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Linya
authors.initials: L
authors.lastname: You
authors.affiliation: The Rosalind & Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada; Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Kezhi
authors.initials: K
authors.lastname: Yan
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Zou
authors.affiliation: National Research Council Canada, Montreal, Quebec, Canada.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: The Rosalind & Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: The Rosalind & Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Bertos
authors.affiliation: The Rosalind & Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Biochemistry, McGill University, Montreal, Quebec, Canada; McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.affiliation: National Research Council Canada, Montreal, Quebec, Canada.
authors.forename: Edwin
authors.initials: E
authors.lastname: Wang
authors.affiliation: The Rosalind & Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Biochemistry, McGill University, Montreal, Quebec, Canada; McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Xiang-Jiao
authors.initials: XJ
authors.lastname: Yang
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins; D018891:Dentate Gyrus / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D044127:Epigenesis, Genetic / Q000235:genetics*; D006624:Hippocampus / Q000254:growth & development / Q000473:pathology; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009024:Morphogenesis / Q000235:genetics*; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D016548:Prosencephalon / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006657:Histones; D020825:T-Box Domain Proteins; C000597967:BRPF1 protein, mouse; D000092468:Bromodomain Containing Proteins; C491198:Eomes protein, mouse; C487137:KAT6B protein, human; C511438:MOZ protein, mouse