title: Trrap-dependent histone acetylation specifically regulates cell-cycle gene transcription to control neural progenitor fate decisions.
abstract: Fate decisions in neural progenitor cells are orchestrated via multiple pathways, and the role of histone acetylation in these decisions has been ascribed to a general function promoting gene activation. Here, we show that the histone acetyltransferase (HAT) cofactor transformation/transcription domain-associated protein (Trrap) specifically regulates activation of cell-cycle genes, thereby integrating discrete cell-intrinsic programs of cell-cycle progression and epigenetic regulation of gene transcription in order to control neurogenesis. Deletion of Trrap impairs recruitment of HATs and transcriptional machinery specifically to E2F cell-cycle target genes, disrupting their transcription with consequent cell-cycle lengthening specifically within cortical apical neural progenitors (APs). Consistently, Trrap conditional mutants exhibit microcephaly because of premature differentiation of APs into intermediate basal progenitors and neurons, and overexpressing cell-cycle regulators in vivo can rescue these premature differentiation defects. These results demonstrate an essential and highly specific role for Trrap-mediated histone regulation in controlling cell-cycle progression and neurogenesis.
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Alicia
authors.initials: A
authors.lastname: Tapias
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Zhong-Wei
authors.initials: ZW
authors.lastname: Zhou
authors.affiliation: Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, 1-7 Beichen West Road, Chaoyang District, Beijing 100101, P.R. China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, P.R. China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, 1-7 Beichen West Road, Chaoyang District, Beijing 100101, P.R. China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, P.R. China.
authors.forename: Zechen
authors.initials: Z
authors.lastname: Chong
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Groth
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
authors.forename: Wieland
authors.initials: W
authors.lastname: Huttner
authors.affiliation: International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France.
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.affiliation: Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, 1-7 Beichen West Road, Chaoyang District, Beijing 100101, P.R. China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, P.R. China.
authors.forename: Yun-Gui
authors.initials: YG
authors.lastname: Yang
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany; Faculty of Biology and Pharmacy, Friedrich Schiller University of Jena, Fuerstengraben 26, 07743 Jena, Germany. Electronic address: zqwang@fli-leibniz.de.
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005260:Female; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008962:Models, Theoretical; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C113829:transformation-transcription domain-associated protein; D051548:Histone Acetyltransferases