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Diagnostic Utility of DNA Methylation Analysis in Genetically Unsolved Pediatric Epilepsies and CHD2 Episignature Refinement

ABSTRACT: Sequence-based genetic testing identifies causative variants in ~50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269416 | GEO | 2024/06/13

REPOSITORIES: GEO

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Diagnostic Utility of DNA Methylation Analysis in Genetically Unsolved Pediatric Epilepsies and CHD2 Episignature Refinement

Project description:Diagnostic Utility of DNA Methylation Analysis in Genetically Unsolved Pediatric Epilepsies and CHD2 Episignature Refinement

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Novel parent-of-origin specific differentially methylated loci on chromosome 16

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Project description:CHD2 variants

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Episignatures stratifying ADNP syndrome show modest correlation with phenotype [RNA-seq]

Project description:We conducted an independent study on 24 individuals with ADNP syndrome and replicated the existence of the two mutation-dependent ADNP episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of ADNP syndrome.

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Episignatures stratifying ADNP syndrome show modest correlation with phenotype [Methylation]

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Enhanced epigenetic profiling of classical human monocytes reveals a specific signature of healthy aging in the DNA methylome

Project description:The impact of healthy aging on molecular programming of immune cells is poorly understood. Here, we report comprehensive characterization of healthy aging in human classical monocytes, with a focus on epigenomic, transcriptomic, and proteomic alterations, as well as the corresponding proteomic and metabolomic data for plasma, using healthy cohorts of 20 young and 20 older males (~27 and ~64 years old on average). For each individual, we performed eRRBS-based DNA methylation profiling, which allowed us to identify a set of age-associated differentially methylated regions (DMRs) – a novel, cell-type specific signature of aging in DNA methylome. Hypermethylation events were associated with H3K27me3 in the CpG islands near promoters of lowly-expressed genes, while hypomethylated DMRs were enriched in H3K4me1 marked regions and associated with age-related increase of expression of the corresponding genes, providing a link between DNA methylation and age-associated transcriptional changes in primary human cells.

2022-02-16 | PXD021821 | Pride

Regulation of CHD2 expression by a long noncoding RNA is essential for mammalian development

Project description:Long noncoding RNAs (lncRNAs) are enriched in regions flanking transcription- and chromatin-associated genes, but the functional importance of such co-location events is largely unclear. Chromodomain helicase DNA binding protein 2 (Chd2) is chromatin remodeller with various reported functions in cell differentiation and DNA damage response. Heterozygous mutations in human CHD2 have been implicated in epilepsy, neurodevelopmental delay, and intellectual disability. Here we show that Chaser, a highly conserved long noncoding RNA transcribed from a region in close proximity to the transcription start site of Chd2 and on the same strand, acts in concert with the CHD2 protein to maintain proper Chd2 expression levels. Loss of Chaser in mice leads to substantially increased levels of Chd2 mRNA and protein in the embryo and in adult tissues, early postnatal lethality in homozygous animals, and severe growth retardation in heterozygotes. Mechanistically, over-production of Chd2 induced by loss of Chaser leads to increased transcriptional interference by inhibiting promoters found downstream of highly expressed genes. We further show that Chaser production represses Chd2 expression solely in cis, and the phenotypic consequences of Chaser loss are rescued when Chd2 is perturbed as well. Targeting Chaser is thus a potentially viable strategy for increasing CHD2 levels in haploinsufficient individuals.

2019-09-23 | GSE124375 | GEO

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Project description:Chronic pain is a global public health problem, but the underlying molecular mechanisms are not fully understood. Here we examine genome-wide DNA methylation, first in 50 identical twins discordant for heat pain sensitivity and then in 50 further unrelated individuals. Whole blood DNA methylation was characterized at 5.2 million loci by MeDIP-sequencing and assessed longitudinally to identify differentially methylated regions associated with high or low pain-sensitivity (pain-DMRs). Nine meta-analysis pain-DMRs show robust evidence for association (false discovery rate 5%) with the strongest signal in the pain gene TRPA1 (P=1.2M-CM-^W10-13). Several pain-DMRs show longitudinal stability consistent with susceptibility effects, have similar methylation levels in brain, and altered expression in skin. Our approach identifies epigenetic changes in both novel and established candidate genes that provide molecular insights into pain and may generalize to other complex traits. MeDIP-sequencing in 100 individulas using a 2 stage design: paired-end MeDIP-seq in 50 monozygotic twins and single-end MeDIP-seq in 50 unrelated individuals.

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Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities.

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CHD2 maintains spermatogonial self-renewal by promoting chromatin activity and mRNA stability

Project description:Chromodomain Helicase DNA-binding Domain 2 (CHD2), as a chromatin remodeling factor, was shown to be involved in the regulation of gene expression in embryonic development, neurodevelopment and myelopoiesis. However, its role in male germ cell development has not been elucidated. Here, we confirmed that CHD2 is abundantly expressed throughout the male germ cells with the highest expression in the spermatocytes of meiosis I. By constructing a heterozygous gene knockout mouse model of Chd2 (Chd2+/-), we demonstrated that CHD2 haploinsufficiency resulted in testicular developmental delay and increased rate of abnormal sperm in mice. DNA damage repair, synapsis and cell proliferation during spermatogenesis are impaired in Chd2+/- mice. In vitro experiments in C18-4 and GC-1 spg cells showed that CHD2 knockdown inhibits spermatogonial self-renewal. Mechanically, CHD2 maintained the enrichment of H3K4me3 in Ccnb1 and Ccnd2 promoter consequently promoting the transcription of Ccnb1 and Ccnd2. In addition, by interacting with cleavage stimulation factor CSTF3, CHD2 binds Oct4, Plzf mRNA and upregulates the expression of OCT4 and PLZF by improving mRNA stability. This is the first time to reveal the role and mechanism of CHD2 in maintaining spermatogonial self-renewal by promoting chromatin activity and mRNA stability in spermatogenesis.

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