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

Publication ,  Journal Article
Khazaei, S; Chen, CCL; Andrade, AF; Kabir, N; Azarafshar, P; Morcos, SM; França, JA; Lopes, M; Lund, PJ; Danieau, G; Worme, S; Adnani, L ...
Published in: Cell
March 16, 2023

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.

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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

March 16, 2023

Volume

186

Issue

6

Start / End Page

1162 / 1178.e20

Location

United States

Related Subject Headings

  • Neuroinflammatory Diseases
  • Mice
  • Histones
  • Developmental Biology
  • DNA Modification Methylases
  • DNA Methyltransferase 3A
  • DNA Methylation
  • DNA (Cytosine-5-)-Methyltransferases
  • Animals
  • 32 Biomedical and clinical sciences
 

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Khazaei, S., Chen, C. C. L., Andrade, A. F., Kabir, N., Azarafshar, P., Morcos, S. M., … 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
Khazaei, Sima, Carol C. L. Chen, Augusto Faria Andrade, Nisha Kabir, Pariya Azarafshar, Shahir M. Morcos, Josiane Alves França, et al. “Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration.Cell 186, no. 6 (March 16, 2023): 1162-1178.e20. https://doi.org/10.1016/j.cell.2023.02.023.
Khazaei S, Chen CCL, Andrade AF, Kabir N, Azarafshar P, Morcos SM, et al. Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration. Cell. 2023 Mar 16;186(6):1162-1178.e20.
Khazaei, Sima, et al. “Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration.Cell, vol. 186, no. 6, Mar. 2023, pp. 1162-1178.e20. Pubmed, doi:10.1016/j.cell.2023.02.023.
Khazaei S, Chen CCL, Andrade AF, Kabir N, Azarafshar P, Morcos SM, França JA, Lopes M, Lund PJ, Danieau G, Worme S, Adnani L, Nzirorera N, Chen X, Yogarajah G, Russo C, Zeinieh M, Wong CJ, Bryant L, Hébert S, Tong B, Sihota TS, Faury D, Puligandla E, Jawhar W, Sandy V, Cowan M, Nakada EM, Jerome-Majewska LA, Ellezam B, Gomes CC, Denecke J, Lessel D, McDonald MT, Pizoli CE, Taylor K, Cocanougher BT, Bhoj EJ, Gingras A-C, Garcia BA, Lu C, Campos EI, Kleinman CL, Garzia L, Jabado N. Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration. Cell. 2023 Mar 16;186(6):1162-1178.e20.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

March 16, 2023

Volume

186

Issue

6

Start / End Page

1162 / 1178.e20

Location

United States

Related Subject Headings

  • Neuroinflammatory Diseases
  • Mice
  • Histones
  • Developmental Biology
  • DNA Modification Methylases
  • DNA Methyltransferase 3A
  • DNA Methylation
  • DNA (Cytosine-5-)-Methyltransferases
  • Animals
  • 32 Biomedical and clinical sciences