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

Par Conseil national de recherches du Canada

DOITrouver le DOI : https://doi.org/10.1371/journal.pgen.1005034
AuteurRechercher : ; Rechercher : ; Rechercher : 1; Rechercher : ; Rechercher : ; Rechercher : ; Rechercher : 2; Rechercher :
Affiliation du nom
  1. Conseil national de recherches du Canada
  2. Conseil national de recherches du Canada. Thérapeutique en santé humaine
FormatTexte, Article
Sujetacyltransferase; 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
Résumé
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.
Date de publication
Maison d’éditionPLOS
Dans
  • PLoS Genetics 11, nº 3, e1005034.
Langueanglais
Publications évaluées par des pairsOui
Numéro NPARC21275631
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Identificateur de l’enregistrement6267721f-7307-4e64-91b2-dbfa109d532d
Enregistrement créé2015-07-14
Enregistrement modifié2021-09-17
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