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Series GSE225372 Query DataSets for GSE225372
Status Public on Nov 08, 2023
Title Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional disruptions
Organism Mus musculus
Experiment type Methylation profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
Summary Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNMT3A, a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a DNMT3A P900L/+ mouse mimicking a mutation with mild-to-moderate severity, and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes which may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease.
Overall design Low and Hi-depth whole genome bisulfite sequencing (WGBS) of mouse cerebral cortex from 8-week WT and DNMT3A mutant mice

Low-depth whole genome bisulfite sequencing (WGBS) of mouse brain region tissue from 8-week WT and DNMT3A mutant mice

Chromatin immunoprecipitation DNA sequencing (ChIP-seq) for histone modification H3K27ac in 8-week wildtype and DNMT3A mutant mouse cerebral cortex

Comparative gene expression profiling analysis of total RNA-seq data from 8-week WT and DNMT3A mutant mouse cerebral cortex

Chromatin immunoprecipitation DNA sequencing (ChIP-seq) for MeCP2 in 8-week wildtype and DNMT3A mutant mouse cerebral cortex
Contributor(s) Beard DC, Wu DY, Hamagami N, Erickson A, Gabel HW
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Submission date Feb 15, 2023
Last update date Nov 09, 2023
Contact name Diana Christian Beard
Organization name Washington University in St. Louis
Department Neuroscience
Lab Harrison Gabel
Street address 660 S. Euclid Ave.
City St. Louis
State/province Missouri
ZIP/Postal code 63110
Country USA
Platforms (3)
GPL16417 Illumina MiSeq (Mus musculus)
GPL19057 Illumina NextSeq 500 (Mus musculus)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (100)
GSM7047606 WGBS_P900L_F_306-2
GSM7047607 WGBS_P900L_F_306-3
GSM7047608 WGBS_P900L_M_706-5
BioProject PRJNA935357

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE225372_BrainRegion_WGBS.xlsx 124.4 Kb (ftp)(http) XLSX
GSE225372_P900Lhyper.bed.gz 2.0 Kb (ftp)(http) BED
GSE225372_P900Lhypo.bed.gz 33.3 Kb (ftp)(http) BED
GSE225372_R878Hhyper.bed.gz 1.8 Kb (ftp)(http) BED
GSE225372_R878Hhypo.bed.gz 157.3 Kb (ftp)(http) BED
GSE225372_RAW.tar 7.6 Gb (http)(custom) TAR (of BED)
GSE225372_RNA_counts.csv.gz 1.1 Mb (ftp)(http) CSV
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record
Processed data provided as supplementary file

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