Comparative DNA methylation among females with neurodevelopmental disorders and seizures identifies TAC1 as a MeCP2 target gene

SummaryMutations in DNA methyltransferase 3A (DNMT3A) have been detected in autism and related disorders, but how these mutations disrupt nervous system function is unknown. Here we define the effects of neurodevelopmental disease-associated DNMT3A mutations. We show that diverse mutations affect different aspects of protein activity yet lead to shared deficiencies in neuronal DNA methylation. Heterozygous DNMT3A knockout mice mimicking DNMT3A disruption in disease display growth and behavioral alterations consistent with human phenotypes. Strikingly, in these mice we detect global disruption of neuron-enriched non-CG DNA methylation, a binding site for the Rett syndrome protein MeCP2. Loss of this methylation leads to enhancer and gene dysregulation that overlaps with models of Rett syndrome and autism. These findings define effects of DNMT3A haploinsufficiency in the brain and uncover disruption of the non-CG methylation pathway as a convergence point across neurodevelopmental disorders.

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Identification of a DNA Methylation Episignature in the 22q11.2 Deletion Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms22168611 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8611

Author(s):

Kathleen Rooney ◽

Michael A. Levy ◽

Sadegheh Haghshenas ◽

Jennifer Kerkhof ◽

Daniela Rogaia ◽

...

Keyword(s):

Dna Methylation ◽

Neurodevelopmental Disorders ◽

Clinical Presentation ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

Mild Intellectual Disability ◽

Genomic Disorder ◽

22Q11.2 Deletion ◽

Chromatin Remodelers ◽

Genome Wide

The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20–40 genes, respectively. The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.

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FHL2 promoter DNA methylation increases with chronological age in joint tissues and impacts target gene expression

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2021.02.409 ◽

2021 ◽

Vol 29 ◽

pp. S310

Author(s):

R.C. Fulea ◽

L. Reynard ◽

D. Young ◽

G. Bou-Gharios

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Target Gene ◽

Chronological Age ◽

Target Gene Expression ◽

Promoter Dna Methylation ◽

Promoter Dna

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DNA Methylation of miR-122 Aggravates Oxidative Stress in Colitis Targeting SELENBP1 Partially by p65NF-κB Signaling

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/5294105 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

Jianan Bai ◽

Junchi Yu ◽

Jintian Wang ◽

Bingyan Xue ◽

Na He ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Methylation ◽

Target Gene ◽

Bisulfite Sequencing ◽

Cpg Islands ◽

Colonic Tissue ◽

Tissue Samples ◽

Benzene Sulfonic Acid ◽

Ht 29 ◽

Colitis Model

Aberrant microRNA (miRNA) expressions contribute to the development and progression of various diseases, including Crohn’s disease (CD). However, the accurate mechanisms of miRNAs in CD are definitely unclear. We employed colonic tissue samples from normal volunteers and CD patients, an acute mice colitis model induced by 2,4,6-trinitro-benzene-sulfonic acid (TNBS), and a cellular oxidative stress model induced by H2O2 in HT-29 cells to determine the effects of oxidative stress on expressions of miR-122, selenium-binding protein 1 (SELENBP1, SBP1), p65 nuclear factor κB (p65NF-κB) signaling, and DNA methylation. We found that SBP1 was mainly located on epithelial cells and was significantly increased in patients with active CD. SBP1 was the target gene of miR-122. miR-122 expression was downregulated while SBP1 expression was upregulated under TNBS-induced colitis or oxidative stress. Pre-miR-122 or siRNA SBP1 (si-SBP1) treatment ameliorated acute TNBS-induced colitis and H2O2-induced oxidative stress. Cotreatment of pre-miR-122 and si-SBP1 enhanced these effects. Besides, pre-miR-122 and si-SBP1 obviously activated the p65NF-κB signaling by phosphorylation of IκBα. Bisulfite sequencing of the CpG islands in the promoter region of miR-122 showed that CpG methylation was significantly increased under oxidative stress. Treating cells with 5′-AZA which was well known as a DNA-demethylating agent significantly increased miR-122 expression. Our results suggest that oxidative stress-induced DNA methylation of miR-122 aggravates colitis targeting SELENBP1 partially by p65NF-κB signaling and may promote the progression of CD.

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Comethyl: A network-based methylome approach to investigate the multivariate nature of health and disease

10.1101/2021.07.14.452385 ◽

2021 ◽

Author(s):

Charles E. Mordaunt ◽

Julia S. Mouat ◽

Rebecca J. Schmidt ◽

Janine M. LaSalle

Keyword(s):

Dna Methylation ◽

Health Disparities ◽

Neurodevelopmental Disorders ◽

Association Studies ◽

Health Sciences ◽

Autism Spectrum ◽

Associate Professor ◽

System Level ◽

Genome Wide Association Studies ◽

Medical Microbiology

AbstractHealth outcomes are frequently shaped by difficult to dissect inter-relationships between biological, behavioral, social, and environmental factors. DNA methylation patterns reflect such multi-variate intersections, providing a rich source of novel biomarkers and insight into disease etiologies. Recent advances in whole-genome bisulfite sequencing (WGBS) enable investigation of DNA methylation over all genomic CpGs, but existing bioinformatic approaches lack accessible system-level tools. Here, we develop the R package Comethyl, for weighted gene correlation network analysis (WGCNA) of user-defined genomic regions that generates modules of comethylated regions, which are then tested for correlations with sample traits. First, regions are defined by CpG genomic location or regulatory annotation and filtered based on CpG count, sequencing depth, and variability. Next, correlation networks are used to find modules of interconnected nodes using methylation values within the selected regions. Each module containing multiple comethylated regions is reduced in complexity to a single eigennode value, which is then tested for correlations with experimental metadata. Comethyl has the ability to cover the noncoding regulatory regions of the genome with high relevance to interpretation of genome-wide association studies and integration with other types of epigenomic data. We demonstrate the utility of Comethyl on a dataset of male cord blood samples from newborns later diagnosed with autism spectrum disorder (ASD) versus typical development. Comethyl successfully identified an ASD-associated module containing gene regions with brain glial functions. Comethyl is expected to be useful in uncovering the multi-variate nature of health disparities for a variety of common disorders. Comethyl is available at github.com/cemordaunt/comethyl.Description of the AuthorsCharles E. Mordaunt, Ph.D. developed Comethyl while a postdoctoral fellow in the department of Medical Microbiology and Immunology at UC Davis. He is currently a Computational Biologist at GSK.Julia S. Mouat is a doctoral student in the Integrative Genetics and Genomics graduate group at UC Davis with interests in health disparities and intergenerational epigenetic risk factors for autism spectrum disorders.Rebecca J. Schmidt, Ph.D. is an Associate Professor of Public Health Sciences at UC Davis, with expertise in the use of epigenetics in epidemiology and neurodevelopmental disorders.Janine M. LaSalle, Ph.D. is a Professor of Medical Microbiology and Immunology, Co-Director of the Perinatal Origins of Disparities Center, and Deputy Director of the Environmental Health Sciences Center at UC Davis, with expertise in epigenomics and neurodevelopmental disorders.

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DNA methylation and gene expression profiles to identify childhood atopic asthma associated genes

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01655-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Rui Chen ◽

Li-Zhen Piao ◽

Ling Liu ◽

Xiao-Fei Zhang

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Mirna Target ◽

Target Gene ◽

Atopic Asthma ◽

Mirna Target Gene ◽

Kegg Pathways ◽

Gene Regulatory

Abstract Background Asthma is a chronic inflammatory disorder of the airways involving many different factors. This study aimed to screen for the critical genes using DNA methylation/CpGs and miRNAs involved in childhood atopic asthma. Methods DNA methylation and gene expression data (Access Numbers GSE40732 and GSE40576) were downloaded from the Gene Expression Omnibus database. Each set contains 194 peripheral blood mononuclear cell (PBMC) samples of 97 children with atopic asthma and 97 control children. Differentially expressed genes (DEGs) with DNA methylation changes were identified. Pearson correlation analysis was used to select genes with an opposite direction of expression and differences in methylation levels, and then Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. Protein–protein interaction network and miRNA–target gene regulatory networks were then constructed. Finally, important genes related to asthma were screened. Results A total of 130 critical DEGs with DNA methylation changes were screened from children with atopic asthma and compared with control samples from healthy children. GO and KEGG pathway enrichment analysis found that critical genes were primarily related to 24 GO terms and 10 KEGG pathways. In the miRNA–target gene regulatory networks, 9 KEGG pathways were identified. Analysis of the miRNA–target gene network noted an overlapping KEGG signaling pathway, hsa04060: cytokine-cytokine receptor interaction, in which the gene CCL2, directly related to asthma, was involved. This gene is targeted by eight asthma related miRNAs (hsa-miR-206, hsa-miR-19a, hsa-miR-9,hsa-miR-22, hsa-miR-33b, hsa-miR-122, hsa-miR-1, and hsa-miR-23b). The genes IL2RG and CCl4 were also involved in this pathway. Conclusions The present study provides a novel insight into the underlying molecular mechanism of childhood atopic asthma.

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DNA methylation analysis for screening and diagnostic testing in neurodevelopmental disorders

Essays in Biochemistry ◽

10.1042/ebc20190056 ◽

2019 ◽

Vol 63 (6) ◽

pp. 785-795 ◽

Cited By ~ 2

Author(s):

David E. Godler ◽

David J. Amor

Keyword(s):

Dna Methylation ◽

Neurodevelopmental Disorders ◽

Diagnostic Testing ◽

Direct Analysis ◽

Analytical Sensitivity ◽

Methylation Analysis ◽

Genome Wide ◽

Long Read ◽

Indirect Analysis ◽

Low Coverage

Abstract DNA methylation (mDNA) plays an important role in the pathogenesis of neurodevelopmental disorders (NDDs), however its use in diagnostic testing has been largely restricted to a handful of methods for locus-specific analysis in monogenic syndromes. Recent studies employing genome-wide methylation analysis (GWMA) have explored utility of a single array-based test to detect methylation changes in probands negative by exome sequencing, and to diagnose different monogenic NDDs with defined epigenetic signatures. While this may be a more efficient approach, several significant barriers remain. These include non-uniform and low coverage of regulatory regions that may have CG-rich sequences, and lower analytical sensitivity as compared with locus-specific analyses that may result in methylation mosaicism not being detected. A major challenge associated with the above technologies, regardless of whether the analysis is locus specific or genome wide, is the technical bias introduced by indirect analysis of methylation. This review summarizes evidence from the most recent studies in this field and discusses future directions, including direct analysis of methylation using long-read technologies and detection of 5-methylcytosine (5-mC or total mDNA) and 5-hydroxymethylacytosine (5-hmC) as biomarkers of NDDs.

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