. 2023 Mar 16;186(6):1162-1178.e20.

doi: 10.1016/j.cell.2023.02.023.

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

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.

PMID: 36931244
PMCID: PMC10112048
DOI: 10.1016/j.cell.2023.02.023

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

Sima Khazaei et al. Cell. 2023.

. 2023 Mar 16;186(6):1162-1178.e20.

doi: 10.1016/j.cell.2023.02.023.

Authors

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.

PMID: 36931244
PMCID: PMC10112048
DOI: 10.1016/j.cell.2023.02.023

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.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

**Figure 1.. Germline knock-in of H3.3G34R/V/W results in distinct developmental defects.**
A. Left: amino acid depiction of H3.3 glycine 34 (G, hydrophobic) substitution to arginine (R, basic), valine (V, hydrophobic) or tryptophan (W, aromatic). Right: schematic representation of the derivation of H3.3G34R/V/W direct knock-in mice. Single-guide RNA (sgRNA) targeting exon 2 of *H3f3a* is represented by the red box, and the ssODN homology-directed repair (HDR) donor sequence is shown inside the gray box. The HDR template contained the G-to-R/V/W nucleotide substitutions at the G34 codon (red box) and the three silent PAM-blocking mutations (black boxes). Cas9 protein, sgRNA, and ssODN were microinjected into 2- to 4-cell embryos to obtain mosaic founder mice (F0) and backcrossed to two genetic strains to obtain true heterozygous generation 1 (G1) founders. B. Immunohistochemistry staining for H3.3G34R/V/W in DKI mutant mice. C. G34R/V/W mice show distinct and overlapping developmental phenotypes. Right: bar chart depicting penetrance of the observed phenotypes for each G34 mutant, > 10 mice were sampled for each genotype and phenotype combination. D. Body weight of G34 mutant and indel mice represented as ratios normalized to WT mice. n: cumulative number of mice. Representative pictures of WT and G34W mice at P7 and 5 months of age. E. Kaplan-Meier curves for cumulative survival rates of male G34 mutants and controls, n: cumulative number of mice.

**Figure 2.. G34R/V mice show abnormal motor functions and progressive microcephaly.**
A. Adult WT and G34R mice exhibiting hind- and fore-limb clasping. Right: quantitative measure of hindlimb clasping score for G34R mice at adolescence (< 8 weeks) and adult (> 8 weeks), compared to G34V/W and controls (n > 10). Each mouse is plotted individually. Dashed lines: median. Dotted lines: quartiles. Student’s t-test. **** P < 0.0001 and n.s.: non-significant. B. Adult G34R/V show impaired motor coordination and balance compared to G34W and control mice (n > 10). The data is presented as means ± SD. Two-way ANOVA. ***P < 0.001, **** P < 0.0001 and n.s.: non-significant. C. Adult G34R and G34V mutants show hypoactivity in open field test compared to G34W and control animals (n > 6). Each mouse is plotted individually. Dashed and dotted horizontal lines indicate the median and quartiles, respectively. Student’s t-test. ***P < 0.001 and n.s.: non-significant. D. G34R animals show abnormal gait shown by representative digitized mice footprints, as recorded during the CatWalk test of WT (upper) and G34R (lower) littermates. RF, right front; RH, right hind; LF, left front; LH, left hind. E. Image and brain weight of adult G34 mutant mice showing progressive microcephaly in G34R animals (n > 10). Each mouse is plotted individually and as means ± SD. Student’s t-test. *P < 0.05, **P < 0.01, **** P < 0.0001 and n.s.: non-significant.F. Nissl staining of midsagittal cerebral cortex of control and G34 mutant mice showing thinning of L5/6 in G34R animals. Top panel: Cresyl Violet, bottom panel: scored cortical cell layers. Below, quantification of cerebral cortex layers (L5, layer 5; L6, layer 6) areas of control (n=4) and G34 mutant mice (G34R n=3, G34V n=2, G34W n=3) using the Cresyl Violet (Nissl staining). Line: mean. Student’s t-test. **P < 0.01, **** P < 0.0001 and n.s.: non-significant. G. Representative Nissl staining of midsagittal brain slices of control and G34 mutant cerebellum. Note the simplified cerebellum foliation in G34R brain (black arrowheads). H. Representative confocal images of cerebellar para-sagittal sections from control and G34R mice stained for Calbindin (green), a marker of Purkinje neurons. Left: 10X. Right: 20X. The white hatched areas (inset) of P7 and 12-month cerebellar images were used for quantification (n=4) (upper panel). The result of each mouse is plotted individually and as means ± SD. Student’s t-test. ***P < 0.001 and n.s.: non- significant.

**Figure 3.. G34R leads to abnormal accumulation of microglia and depletion of neurons.**
A. Volcano plot depicting differentially expressed genes assayed by bulk transcriptome comparing G34R to WT cortex at P7 (n = 4) and 10W (n = 3). Differentially expressed genes are labelled in red (up-reg.) and blue (down-reg.) using log2FC > 1, adjusted p value < 0.05, normalized mean expression > 100. B. Heatmap of significantly enriched (adjusted p value < 0.05) normalized enrichment scores (NES) of postnatal forebrain cell types of 10W G34 mutants compared with WT (n ≥ 2) by gene set enrichment analysis (GSEA). RGC: radial glial cell. C. G34R shows strong enrichment of disease-associated, but not homeostatic, microglia, and strong depletion of L5/L6 glutaminergic neurons. Heatmap of significantly enriched (adjusted p-value < 0.05) normalized enrichment score (NES) of damage-associated microglia signatures (left) and adult neuronal cell types (right) of G34 mutants compared with WT (n ≥ 2) by gene set enrichment analysis. MGE; medial ganglionic eminence-derived inhibitory GABAergic interneurons, CGE; caudal ganglionic eminence-derived inhibitory GABAergic interneurons. D. G34R cortex shows microglial infiltration and reactive astrocytes, concurrent with depletion of deep cortical neurons. Left: representative immunohistochemical staining of microglia (Iba1) and layer V neuronal marker (Oct6), and double immunofluorescence staining of neurons (NeuN) and astrocytes (GFAP) in cerebral cortex sections from adult mice of control and G34 mutant mice. Right: related quantification of Iba1 (WT n=8, G34R n=7, G34V n=5, and G34W n=7) GFAP (WT n=6, G34R n=4, G34V n=2 and G34W n=3) and Oct6 (WT n=7, G34R n=6, G34V n=4, and G34W n=7). Each mouse is plotted individually and as means ± SD. One-way ANOVA test. *P < 0.05, **P < 0.01, ***P < 0.001, and n.s.: non-significant.

**Figure 4.. G34R histone tails are depleted of H3K36me2/3 and impaired for DNMT3A recruitment.**
A. Waterfall plot depicting relative *cis* differences of histone H3K36 methylation levels on G34-mutant H3.3 histone tails compared to non-mutated H3.3 measured by histone PTM mass spectrometry. Histones were extracted from murine DKI G34R/V/W NPCs (3 biological replicate, 2 technical replicates). Note: H3K36 di- and tri-methylation is severely depleted in G34R, compared to G34V/W (p-value depicts significance derived from student pairwise t-test). B. Similar waterfall plot as panel A, depicting H3K27 methylation *cis* differences on G34-mutant H3.3 histone tails compared to non-mutated H3.3, as measured by histone PTM mass spectrometry. C. Bubble plot depicting BioID interaction frequency of G34-mutant histones (bait) with chromatin modifiers (prey) detected using MS in G34R/V/W and H3.3 WT expressing U2-OS lines (n=2). Note the decrease interaction with DNMT3A and DNMT3B in G34R histones. D. Immunoprecipitation/immunoblot confirmation of decrease DNMT3A (bait) interaction with G34R histones in C3H10T1/2 cell lines exogenously expressing FLAG-tagged H3.3 WT and G34-mutant histones (prey) (n=2). * Denotes p < 0.05, student’s t-test.

**Figure 5.. G34R re-distribute DNMT3A localization, causing loss of CH methylation at intergenic regions.**
A. Schema depicting post-natal expression pattern of *Dnmt3a* and accumulation of mCH/mCG levels in the developing murine cortex. B. Genome browser snapshot depicting G34R-mediated epigenomic change in P7 (H3K36me2, DNMT3A) and 10W adult cortex (mCH, mCG). Upper tracks depict the epigenomic feature in WT cortex and change in G34R is depicted below (loss: grey). C. Metaplot of DNMT3A at called peaks in G34R and WT cortex (n=2). Under, heatmap depicting relative enrichment of H3K36me2 and mCH at DNMT3A peaks. D. Volcano plot depicting CH (left) and CG (right) methylation changes from G34R vs. WT (n = 2) in genome-wide 5kb bins. Hypo- and hyper-methylated bins are scored as p < 0.05 using LIMMA. E. Volcano plot depicting loss of H3K27me3 at gene promoters in P7 and 10W cortex of G34R mice (n = 2). F. Gain of DNMT3A occupancy (blue dots) at gene promoters losing the most H3K27me3 (right side of graph) in G34R cortex. Promoters were ranked by descending Z-score for H3K27me3 (10W G34R vs. WT, red), color dots represent corresponding change in H3K27me3 (pink) and DNMT3A (blue) at P7.

**Figure 6.. Altered DNA methylation is concurrent with transcriptional dysregulation of immune and neuronal genes.**
A. Immune genes are CH-hypomethylated and up-regulated, whereas neuronal genes are CG-hypermethylated and downregulated in G34R cortex. 2D bubble plot depicting change of CH (left) and CG methylation (right) correlated with bulk transcriptional dysregulation in 10W G34R cortex (n = 2). Size of bubble depicts significance of expression dysregulation. Gene ontology annotation of DE genes with immune response function in red, whereas genes annotated with synapse are in blue. B. Heatmap depiction of DNA methylation change (% methylation) and transcriptional change (log2FC) in 10W G34R vs. WT cortex. C. G34R neurons show activation of immune genes and suppression of neuronal genes compared to WT neurons. Density plot showing hypomethylated immune gene enrichment score (y-axis) vs. hypermethylated neuronal gene enrichment score (x-axis) in G34R (pink) and WT (blue) neurons and immune cells from P7 (N = 7848 cells; 3809 G34R, 4039 WT) and 10W (n = 17396 cells; 8539 G34R, 8857 WT) single nuclei transcriptome data. *** p < *2.2e-16,* ** p < *1e-10,* * p < *0.01,* Wilcoxon rank sum test with continuity correction. D. Left: immunofluorescent co-staining of neuron NeuN (green) and complement C1Q (red) depicting G34R-specific accumulation of complement in neuron from substantia nigra region of 10-week brain (63x). Right: immunofluorescent co-staining of postsynaptic protein PSD95 (green) and complement C3 (magenta) from cortex region of 10W brain. E. Immunofluorescent co-staining of PSD95 (green) and microglia marker Iba1 (red) from cortex region of 10W brain. White arrowheads mark colocalization of PSD95 with IBA1 (63x).

**Figure 7.. Neuronal-specific induction of G34R results in neurodegeneration and cortical atrophy.**
A. Schematic representation of the CRISPR G34R-conditional knock-in strategy. An inducible transgene cassette targeting exon 1 of the *H3f3a* gene was inserted using Cas9:gRNA approach. Loxp sites flanked an adenovirus splice-acceptor (SA), mEGFP, and 3x polyA sequences, followed by the H3.3G34R cDNA. Carrier *H3f3a*^+/LGFPLG34R mice were crossed with *Emx1-Cre* or *Foxg1-Cre* mice to generate heterozygous *H3f3a*^+/G34R mice with cortical-specific expression of G34R. B. In situ hybridization of *Emx1* and *Foxg1* genes (Allen Brain Atlas). H3.3G34R IHC staining for representative sagittal section of adult mouse brain from G34R^Emx1 and G34R^Foxg1. CRB: cerebellum. C. Expression levels of *Emx1* and *Foxg1* in murine developing brain atlas. D. Immunofluorescent co-staining of neuronal marker NeuN (green) and G34R (red) in G34R^Emx1 adult mouse brain (20x). E. G34R^Emx1 shows cortex atrophy. Representative image and brain weights (means ± SE) of WT^Emx1 and the reduced cortical region (arrow) of G34R^Emx1 mice. Student’s t-test. **P < 0.01, **** P < 0.0001. F. Immunohistochemical staining of layer V neuronal marker (Oct6) (*top*), neurons (NeuN), and astrocytes (GFAP) (*bottom*) in WT^Emx1 and G34R^Emx1 (20x). Related quantifications, Oct6 (n = 3) and GFAP (n ≥ 4), means ± SD. Student’s t-test. *P < 0.05, **P < 0.01. G. Immunohistochemical staining of microglial marker (Iba1), neuronal postsynaptic protein PSD95, and complement C3 in adult WT^Emx1 and G34R^Emx1 mice (63x). Related quantifications, Iba1 (n ≥ 3) and C3 (n = 3), means ± SD. Student’s t-test. *P < 0.05. H. Model to illustrate dysregulation of epigenetic reprogramming in the postnatal G34R brain, which may account for neuroinflammation and progressive neurodegeneration.

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When the (histone) tail affects the brain.
Typas D. Typas D. Nat Struct Mol Biol. 2023 Apr;30(4):405. doi: 10.1038/s41594-023-00979-9. Nat Struct Mol Biol. 2023. PMID: 37045978 No abstract available.

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

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

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Abstract

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