title: Intellectual disability-associated dBRWD3 regulates gene expression through inhibition of HIRA/YEM-mediated chromatin deposition of histone H3.3.
abstract: Many causal mutations of intellectual disability have been found in genes involved in epigenetic regulations. Replication-independent deposition of the histone H3.3 variant by the HIRA complex is a prominent nucleosome replacement mechanism affecting gene transcription, especially in postmitotic neurons. However, how HIRA-mediated H3.3 deposition is regulated in these cells remains unclear. Here, we report that dBRWD3, the Drosophila ortholog of the intellectual disability gene BRWD3, regulates gene expression through H3.3, HIRA, and its associated chaperone Yemanuclein (YEM), the fly ortholog of mammalian Ubinuclein1. In dBRWD3 mutants, increased H3.3 levels disrupt gene expression, dendritic morphogenesis, and sensory organ differentiation. Inactivation of yem or H3.3 remarkably suppresses the global transcriptome changes and various developmental defects caused by dBRWD3 mutations. Our work thus establishes a previously unknown negative regulation of H3.3 and advances our understanding of BRWD3-dependent intellectual disability.
authors: Institute of Molecular Medicine College of Medicine National Taiwan University, Taipei, Taiwan.
authors: Wei-Yu
authors: WY
authors: Chen
authors: Institute of Molecular Medicine College of Medicine National Taiwan University, Taipei, Taiwan.
authors: Hsueh-Tzu
authors: HT
authors: Shih
authors: Institute of Molecular Medicine College of Medicine National Taiwan University, Taipei, Taiwan.
authors: Kwei-Yan
authors: KY
authors: Liu
authors: Institute of Molecular Medicine College of Medicine National Taiwan University, Taipei, Taiwan.
authors: Zong-Siou
authors: ZS
authors: Shih
authors: Institute of Molecular Medicine College of Medicine National Taiwan University, Taipei, Taiwan.
authors: Li-Kai
authors: LK
authors: Chen
authors: Institute of Molecular Medicine College of Medicine National Taiwan University, Taipei, Taiwan.
authors: Tsung-Han
authors: TH
authors: Tsai
authors: Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan.
authors: Mei-Ju
authors: MJ
authors: Chen
authors: Department of Cell and Molecular Biology, College of Medicine Chang Gung University, Tao-Yuan, Taiwan Molecular Medicine Research Center Chang Gung University, Tao-Yuan, Taiwan.
authors: Hsuan
authors: H
authors: Liu
authors: Molecular Medicine Research Center Chang Gung University, Tao-Yuan, Taiwan Department of Biomedical Sciences and Graduate Institute of Biomedical Sciences, College of Medicine Chang Gung University, Tao-Yuan, Taiwan.
authors: Bertrand Chin-Ming
authors: BC
authors: Tan
authors: Bio-Industrial Mechatronics Engineering, National Taiwan University, Taipei, Taiwan.
authors: Chien-Yu
authors: CY
authors: Chen
authors: Institute of Molecular Medicine College of Medicine National Taiwan University, Taipei, Taiwan.
authors: Hsiu-Hsiang
authors: HH
authors: Lee
authors: Centre de Génétique et de Physiologie Moléculaire et Cellulaire CNRS UMR5534 Université Claude Bernard Lyon 1, Villeurbanne, France.
authors: Benjamin
authors: B
authors: Loppin
authors: Institute of Regenerative medicine and Biotherapy (IRMB) Inserm U1203 Saint-Eloi Hospital, CHRU Montpellier, France.
authors: Ounissa
authors: O
authors: Aït-Ahmed
authors: Institute of Molecular Medicine College of Medicine National Taiwan University, Taipei, Taiwan Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan Research Center for Developmental Biology and Regenerative Medicine National Taiwan University, Taipei, Taiwan junetai.wu@gmail.com.
authors: June-Tai
authors: JT
authors: Wu
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D056488:Histone Chaperones / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009024:Morphogenesis / Q000235:genetics; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D056488:Histone Chaperones; D006657:Histones; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C502037:BRWD3 protein, human; D000092468:Bromodomain Containing Proteins; C086057:HIRA protein, human; C488124:Hira protein, Drosophila; C406814:UBN1 protein, human; C075160:yem protein, Drosophila
keywords: BRWD3; HIRA; YEM; histone H3.3; intellectual disability