Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration,Cell

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Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration
Cell ( IF 45.5 ) Pub Date : 2023-03-16 , DOI: 10.1016/j.cell.2023.02.023
Sima Khazaei ₁ , Carol C L Chen ₁ , Augusto Faria Andrade ₁ , Nisha Kabir ₁ , Pariya Azarafshar ₁ , Shahir M Morcos ₂ , Josiane Alves França ₃ , Mariana Lopes ₄ , Peder J Lund ₄ , Geoffroy Danieau ₅ , Samantha Worme ₆ , Lata Adnani ₇ , Nadine Nzirorera ₁ , Xiao Chen ₈ , Gayathri Yogarajah ₉ , Caterina Russo ₁₀ , Michele Zeinieh ₁ , Cassandra J Wong ₁₁ , Laura Bryant ₁₂ , Steven Hébert ₁₃ , Bethany Tong ₁₄ , Tianna S Sihota ₁ , Damien Faury ₇ , Evan Puligandla ₁₅ , Wajih Jawhar ₁₆ , Veronica Sandy ₇ , Mitra Cowan ₁₇ , Emily M Nakada ₇ , Loydie A Jerome-Majewska ₁₈ , Benjamin Ellezam ₁₉ , Carolina Cavalieri Gomes ₃ , Jonas Denecke ₂₀ , Davor Lessel ₂₁ , Marie T McDonald ₂₂ , Carolyn E Pizoli ₂₃ , Kathryn Taylor ₂₂ , Benjamin T Cocanougher ₂₄ , Elizabeth J Bhoj ₂₅ , Anne-Claude Gingras ₂₆ , Benjamin A Garcia ₄ , Chao Lu ₂₇ , Eric I Campos ₂ , Claudia L Kleinman ₁₃ , Livia Garzia ₅ , Nada Jabado ₂₈

Affiliation

Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
Cancer 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.
Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Department 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.
Research 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.
Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Canada.
Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Cancer 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.
McGill Integrated Core for Animal Modeling (MICAM), McGill University, Montreal, QC, Canada.
Department 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.
Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC H3T 1C5, Canada.
Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Human Genetics, University Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria.
Division of Medical Genetics, Duke University Hospital, Durham, NC, USA.
Division of Pediatric Neurology, Duke University Hospital, Durham, NC, USA.
Department of Pediatrics, Duke University Hospital, Durham, NC, USA.
Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
Department 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.
Department 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.

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.

中文翻译：

H3.3G34 中的单一替换改变 DNMT3A 募集，导致进行性神经变性

种系组蛋白 H3.3 氨基酸取代（包括 H3.3G34R/V）会导致严重的神经发育综合征。为了了解这些突变如何影响大脑发育，我们培育了 H3.3G34R/V/W 敲入小鼠，并确定了每种突变的显着不同的发育缺陷。 H3.3G34R 突变体表现出进行性小头畸形和神经变性，伴有疾病相关小胶质细胞的异常积累和并发的神经元耗竭。 G34R 严重降低突变体 H3.3 尾部的 H3K36me2，损害 DNA 甲基转移酶 DNMT3A 的募集及其在染色质上的重新分配。这些变化与补体和其他先天免疫基因的持续表达同时发生，可能是由于非 CG (CH) 甲基化的丧失以及通过异常 CG 甲基化导致的神经元基因启动子的沉默。 G34R 大脑中的补体表达可能导致神经炎症，这可能是进行性神经变性的原因。我们的研究表明，H3.3G34 取代对表观基因组有不同的影响，表观基因组是观察到的不同表型的基础，并揭示了 H3K36me2 和 DNMT3A 依赖性 CH 甲基化在调节产后大脑突触修剪和神经炎症中的潜在作用。

更新日期：2023-03-16

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