The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors

From National Research Council Canada

DOIResolve DOI: https://doi.org/10.1371/journal.pgen.1005034
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Name affiliation
  1. National Research Council of Canada
  2. National Research Council of Canada. Human Health Therapeutics
FormatText, Article
Journal titlePLoS Genetics
ISSN1553-7390
Volume11
Issue3
Article numbere1005034
Subjectacyltransferase; eomesodermin; histone; protein Brpf1; regulator protein; transcription factor Sox2; unclassified drug; animal cell; animal experiment; animal tissue; brain development; Brpf1 gene; cell cycle progression; cell migration; dentate gyrus; developmental gene; epigenetics; forebrain; gene inactivation; hippocampus; histone acetylation; hypoplasia; learning; memory; mouse; nerve cell differentiation; nervous system development; neural stem cell; protein binding; protein depletion; transcription regulation
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.
Publication date
PublisherPLOS
LanguageEnglish
Peer reviewedYes
NPARC number21275631
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