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

Authors

• 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

Publication/Presentation Date

3-16-2023

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.

Volume

186

Issue

6

First Page

1162

Last Page

1178

ISSN

1097-4172

Published In/Presented At

Khazaei, S., Chen, C. C. L., Andrade, A. F., Kabir, N., Azarafshar, P., Morcos, S. M., França, J. A., Lopes, M., Lund, P. J., Danieau, G., Worme, S., Adnani, L., Nzirorera, N., Chen, X., Yogarajah, G., Russo, C., Zeinieh, M., Wong, C. J., Bryant, L., Hébert, S., … Jabado, N. (2023). Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration. Cell, 186(6), 1162–1178.e20. https://doi.org/10.1016/j.cell.2023.02.023

Disciplines

Medicine and Health Sciences | Pediatrics

PubMedID

36931244

Department(s)

Department of Pediatrics

Document Type

Article