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

Sima Khazaei; Carol C L Chen; Augusto Faria Andrade; Nisha Kabir; Pariya Azarafshar; Shahir M Morcos; Josiane Alves França; Mariana Lopes; Peder J Lund; Geoffroy Danieau; Samantha Worme; Lata Adnani; Nadine Nzirorera; Xiao Chen; Gayathri Yogarajah; Caterina Russo; Michele Zeinieh; Cassandra J Wong; Laura Bryant; Steven Hébert; Bethany Tong; Tianna S Sihota; Damien Faury; Evan Puligandla; Wajih Jawhar; Veronica Sandy; Mitra Cowan; Emily M Nakada; Loydie A Jerome-Majewska; Benjamin Ellezam; Carolina Cavalieri Gomes; Jonas Denecke; Davor Lessel; Marie T McDonald; Carolyn E Pizoli; Kathryn Taylor; Benjamin T Cocanougher; Elizabeth J Bhoj; Anne-Claude Gingras; Benjamin A Garcia; Chao Lu; Eric I Campos; Claudia L Kleinman; Livia Garzia; Nada Jabado

doi:10.1016/j.cell.2023.02.023

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

Cell. 2023 Mar 16;186(6):1162-1178.e20. doi: 10.1016/j.cell.2023.02.023.

Authors

Sima Khazaei¹, Carol C L Chen¹, Augusto Faria Andrade¹, Nisha Kabir¹, Pariya Azarafshar¹, Shahir M Morcos², Josiane Alves França³, Mariana Lopes⁴, Peder J Lund⁴, Geoffroy Danieau⁵, Samantha Worme⁶, Lata Adnani⁷, Nadine Nzirorera¹, Xiao Chen⁸, Gayathri Yogarajah⁹, Caterina Russo¹⁰, Michele Zeinieh¹, Cassandra J Wong¹¹, Laura Bryant¹², Steven Hébert¹³, Bethany Tong¹⁴, Tianna S Sihota¹, Damien Faury⁷, Evan Puligandla¹⁵, Wajih Jawhar¹⁶, Veronica Sandy⁷, Mitra Cowan¹⁷, Emily M Nakada⁷, Loydie A Jerome-Majewska¹⁸, Benjamin Ellezam¹⁹, Carolina Cavalieri Gomes³, Jonas Denecke²⁰, Davor Lessel²¹, Marie T McDonald²², Carolyn E Pizoli²³, Kathryn Taylor²², Benjamin T Cocanougher²⁴, Elizabeth J Bhoj²⁵, Anne-Claude Gingras²⁶, Benjamin A Garcia⁴, Chao Lu²⁷, Eric I Campos², Claudia L Kleinman¹³, Livia Garzia⁵, Nada Jabado²⁸

Affiliations

¹ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
² Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
³ Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
⁴ Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
⁵ 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.
⁶ Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
⁷ Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
⁸ 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.
⁹ 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.
¹⁰ Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
¹¹ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
¹² Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹³ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
¹⁴ Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Canada.
¹⁵ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
¹⁶ 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.
¹⁷ McGill Integrated Core for Animal Modeling (MICAM), McGill University, Montreal, QC, Canada.
¹⁸ 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.
¹⁹ Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC H3T 1C5, Canada.
²⁰ Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany.
²¹ 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.
²² Division of Medical Genetics, Duke University Hospital, Durham, NC, USA.
²³ Division of Pediatric Neurology, Duke University Hospital, Durham, NC, USA.
²⁴ Department of Pediatrics, Duke University Hospital, Durham, NC, USA.
²⁵ Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁶ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
²⁷ 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.
²⁸ 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. Electronic address: nada.jabado@mcgill.ca.

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.

Keywords: CH methylation; DNA methylation; DNMT3A; H3.3 G34R/V/W; H3K36me2; complement; neurodegeneration; neuroinflammation; oncohistones; synaptic pruning.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA (Cytosine-5-)-Methyltransferases / genetics
DNA Methylation / genetics
DNA Methyltransferase 3A*
DNA Modification Methylases / genetics
Histones* / metabolism
Mice
Neuroinflammatory Diseases

Substances

DNA (Cytosine-5-)-Methyltransferases
DNA Methyltransferase 3A
DNA Modification Methylases
Histones
Dnmt3a protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding