Deficiency of the chromatin regulator Brpf1 causes abnormal brain development

From National Research Council Canada

DOI	Resolve DOI: https://doi.org/10.1074/jbc.M114.635250
Author	Search for: You, Linya; Search for: Zou, Jinfeng¹; Search for: Zhao, Hong; Search for: Bertos, Nicholas R.; Search for: Park, Morag; Search for: Wang, Edwin¹; Search for: Yang, Xiang-Jiao
Affiliation	National Research Council of Canada. Human Health Therapeutics
Format	Text, Article
Subject	acetylation; amino acids; chromosomes; gene expression; transcription; acetyl transferase; epigenetic mechanisms; histone acetylation; histone acetyltransferases; intellectual disability; multiple genes; neurological disorders; gene expression regulation; chromatin regulator BRPF1; HBO1 protein; histone acetyltransferase; homeodomain protein; lysine acetyltransferase 6A; lysine acetyltransferase 6B; lysine acetyltransferase 7; MORF protein; MOZ protein; protein; transcription factor; transcription factor Foxa1; transcription factor Lhx4; transcription factor TBX5; transcription factor Twist1; zinc finger protein; agenesis; animal experiment; brain cortex; brain development; brain malformation; corpus callosum; corpus callosum agenesis; epigenetics; forebrain; forebrain development; gene; gene expression; gene mutation; genetic transcription; histone acetylation; Hox gene; in vivo study; intellectual impairment; mouse; nervous system development; neurologic disease; Otx1 gene; Robo3 gene
Abstract	Epigenetic mechanisms are important in different neurological disorders, and one such mechanism is histone acetylation. The multivalent chromatin regulator BRPF1 (bromodomainand 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.
Publication date	2015-03-15
Publisher	American Society for Biochemistry and Molecular Biology
In	The Journal of Biological Chemistry 290, no. 11: 7114–7129.
Language	English
Peer reviewed	Yes
NPARC number	21275638
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Record identifier	60120282-8ce1-494d-805b-b95ee4ab9424
Record created	2015-07-14
Record modified	2020-04-22

Date modified:: 2024-12-26