ArticleCell2023
Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration.
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In one paragraph
Article in Cell, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
0numbers the graph read from it
0cells of the map it votes in
50citing papers in PubMed
9.8field-weighted citation impact, top 1% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
50 citing papers in PubMed, 64 citations in OpenAlex.
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- LncRNA Rmst-driven DNMT3A mRNA stabilization through HuR: implications for neuropathic pain therapy.European journal of medical research · 2025Article
- The Bermuda Triangle of paediatric brain cancers: epigenetics, developmental timing window and cell of origin.Cancer metastasis reviews · 2025Review
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Corrections and comments
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Authors and funding
45 authors at 14 institutions in 7 countries.
Sima KhazaeiDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Carol C L ChenDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Augusto Faria AndradeDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Nisha KabirDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Pariya AzarafsharDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Shahir M MorcosGenetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Josiane Alves FrançaDepartment of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Mariana LopesDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
Peder J LundDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
Geoffroy DanieauCancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Division of Orthopedic Surgery, Faculty of Surgery, McGill University, Montreal, QC H3G 1A4, Canada.
Samantha WormeLady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
Lata AdnaniResearch Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Nadine NziroreraDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Xiao ChenDepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Marine College, Shandong University, Weihai 264209, China.
Gayathri YogarajahResearch Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Department of Biochemistry and Molecular Medicine, Université de Montreal, Research Center of the CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada.
Caterina RussoDepartment of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Michele ZeiniehDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Cassandra J WongLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
Laura BryantCenter for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Steven HébertDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
Bethany TongDepartment of Chemistry and Chemical Biology, McMaster University, Hamilton, Canada.
Tianna S SihotaDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Damien FauryResearch Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Evan PuligandlaDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Wajih JawharCancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Child Health and Human Development, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
Veronica SandyResearch Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Mitra CowanMcGill Integrated Core for Animal Modeling (MICAM), McGill University, Montreal, QC, Canada.
Emily M NakadaResearch Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Loydie A Jerome-MajewskaDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.
Benjamin EllezamDepartment of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC H3T 1C5, Canada.
Carolina Cavalieri GomesDepartment of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Jonas DeneckeDepartment of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany.
Davor LesselInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Human Genetics, University Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria.
Marie T McDonaldDivision of Medical Genetics, Duke University Hospital, Durham, NC, USA.
Carolyn E PizoliDivision of Pediatric Neurology, Duke University Hospital, Durham, NC, USA.
Kathryn TaylorDivision of Medical Genetics, Duke University Hospital, Durham, NC, USA.
Benjamin T CocanougherDepartment of Pediatrics, Duke University Hospital, Durham, NC, USA.
Elizabeth J BhojChildren's Hospital of Philadelphia, Philadelphia, PA, USA.
Anne-Claude GingrasDepartment of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
Benjamin A GarciaDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
Chao LuDepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
Eric I CamposGenetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Claudia L KleinmanDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
Livia GarziaCancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Division of Orthopedic Surgery, Faculty of Surgery, McGill University, Montreal, QC H3G 1A4, Canada.
Nada JabadoDepartment of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada. Electronic address: nada.jabado@mcgill.ca.
McGill University Health Centre · CAMcGill University · CADuke University Hospital · USJewish General Hospital · CAWashington University in St. Louis · USChildren's Hospital of Philadelphia · USMount Sinai Hospital · CAUniversidade Federal de Minas Gerais · BRUniversität Hamburg · DEUniversity of Toronto · CACentre Hospitalier Universitaire Sainte-Justine · CAColumbia University Irving Medical Center · USMcMaster University · CAShandong University · CN
Funding
Shared Resources Core 2: Quantitative Proteomics CoreP01CA196539 · NCI · ROCKEFELLER UNIVERSITY · PI YOUNG, MICHAEL WARREN · 2015 to 2024
$17.6MIMMUNOBIOLOGY OF NORMAL AND NEOPLASTIC LYMPHOCYTEST32CA009140 · NCI · UNIVERSITY OF PENNSYLVANIA · PI Malay Haldar, WARREN S PEAR · 1985 to 2026
$16.1MViral modulation of epitranscriptomic mechanismsR01AI118891 · NIAID · WASHINGTON UNIVERSITY · PI GARCIA, BENJAMIN A, WEITZMAN, MATTHEW D. · 2015 to 2025
$5.4MCCL2 and CCR2 as metastatic drivers and therapeutic targets in medulloblastomaR01CA255369 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GARZIA, LIVIA, TAYLOR, MICHAEL D. · 2021 to 2025
$3.9MMolecular basis for aberrant de novo DNA methylation in cancerR01CA266978 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI Karim Jean Armache, Chao Lu · 2022 to 2026
$2.6MRegulation and Function of Histone H3K36 Methylation in Mammalian ChromatinR35GM138181 · NIGMS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI LU, CHAO · 2020 to 2024
$2.0MDuke Creating ADRD Researchers for the Next Generation - Stimulating Access to Research in Residency Program (CARiNG-StARR)"R38AG065762 · NIA · DUKE UNIVERSITY · PI VIERA, ANTHONY J, WHITSON, HEATHER E. · 2020 to 2024
$1.4MNCI NIH HHS P01 CA196539NCI NIH HHS R01 CA255369NCI NIH HHS R01 CA266978NCI NIH HHS T32 CA009140NIAID NIH HHS R01 AI118891NIA NIH HHS R38 AG065762NIGMS NIH HHS R35 GM138181
Abstract
Germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes. To understand how these mutations impact brain development, we generated H3.3G34R/V/W knock-in mice and identified strikingly distinct developmental defects for each mutation. H3.3G34R-mutants exhibited progressive microcephaly and neurodegeneration, with abnormal accumulation of disease-associated microglia and concurrent neuronal depletion. G34R severely decreased H3K36me2 on the mutant H3.3 tail, impairing recruitment of DNA methyltransferase DNMT3A and its redistribution on chromatin. These changes were concurrent with sustained expression of complement and other innate immune genes possibly through loss of non-CG (CH) methylation and silencing of neuronal gene promoters through aberrant CG methylation. Complement expression in G34R brains may lead to neuroinflammation possibly accounting for progressive neurodegeneration. Our study reveals that H3.3G34-substitutions have differential impact on the epigenome, which underlie the diverse phenotypes observed, and uncovers potential roles for H3K36me2 and DNMT3A-dependent CH-methylation in modulating synaptic pruning and neuroinflammation in post-natal brains.
Indexed as
DNA Methyltransferase 3AHistonesAnimalsDNA (Cytosine-5-)-MethyltransferasesDNA MethylationDNA Modification MethylasesMiceNeuroinflammatory DiseasesDNA (Cytosine-5-)-MethyltransferasesDNA Methyltransferase 3ADNA Modification MethylasesDnmt3a protein, mouseHistonesCH methylationcomplementDNA methylationDNMT3AH3.3 G34R/V/WH3K36me2neurodegenerationneuroinflammationoncohistonessynaptic pruning
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.