Background: The chromatin regulator BRPF1 recognizes different epigenetic marks and activates multiple histone acetyltransferases, but little is known about its biological functions in mammals. Results: Forebrain-specific inactivation of the mouse gene causes neocortical abnormalities and partial agenesis of the corpus callosum. Conclusion: Mammalian BRPF1 is important for forebrain development. Significance: This study links a unique chromatin regulator to mammalian brain development.
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.
Background: Deletion of the mouse Brpf1 gene causes embryonic lethality, but the resulting defects await characterization. Results: The vasculature, neural tube, and cell proliferation are abnormal in the mutant. Conclusion: Brpf1 is important for embryo development and cell cycle control. Significance: This study identifies a critical role of a multivalent chromatin regulator in embryogenesis and cell proliferation.
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