scholarly journals Methyl-CpG binding domain 2 (Mbd2) is an Epigenetic Regulator of Autism-Risk Genes and Cognition

2018 ◽  
Author(s):  
Elad Lax ◽  
Sonia DoCarmo ◽  
Yehoshua Enuka ◽  
Daniel M. Sapozhnikov ◽  
Lindsay A. Welikovitch ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Autism Spectrum ◽  
Methylation Pattern ◽  
Binding Domain ◽  
Behavioral Alterations ◽  
Risk Genes ◽  
A Genome ◽  
Epigenetic Regulator ◽  
Neuronal Genes ◽  
Regulatory Dna

AbstractThe Methyl-CpG-Binding Domain Protein family has been implicated in neurodevelopmental disorders. The Methyl-CpG-binding domain 2 (Mbd2) binds methylated DNA and was shown to play an important role in cancer and immunity. Some evidence linked this protein to neurodevelopment. However, its exact role in neurodevelopment and brain function is mostly unknown.Here we show that Mbd2-deficiency in mice (Mbd2−/−) results in deficits in cognitive, social and emotional functions. Mbd2 binds regulatory DNA regions of neuronal genes in the hippocampus and loss of Mbd2 alters the expression of hundreds of genes with a robust down-regulation of neuronal gene pathways. Further, a genome-wide DNA methylation analysis found an altered DNA methylation pattern in regulatory DNA regions of neuronal genes in Mbd2−/− mice. Differentially expressed genes significantly overlap with gene-expression changes observed in brains of Autism Spectrum Disorder (ASD) individuals. Notably, down-regulated genes are significantly enriched for human ortholog ASD risk-genes. Observed hippocampal morphological abnormalities were similar to those found in individuals with ASD and ASD rodent models. Hippocampal Mbd2 knockdown partially recapitulates the behavioral phenotypes observed in Mbd2−/− mice.These findings suggest Mbd2 is a novel epigenetic regulator of genes that are associated with ASD in humans. Mbd2 loss causes behavioral alterations that resemble those found in ASD individuals.

scholarly journals Autism-Associated DNA Methylation at Birth From Multiple Tissues Is Enriched for Autism Genes in the Early Autism Risk Longitudinal Investigation

2021 ◽  
Vol 14 ◽  
Author(s):  
Kelly M. Bakulski ◽  
John F. Dou ◽  
Jason I. Feinberg ◽  
Max T. Aung ◽  
Christine Ladd-Acosta ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Late Pregnancy ◽  
Maternal Blood ◽  
Autism Spectrum ◽  
Epigenetic Mark ◽  
Global Methylation ◽  
Risk Genes ◽  
Longitudinal Investigation ◽  
Research Initiative

Background: Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children. Few ASD studies have considered prospective designs with DNA methylation measured in multiple tissues and tested overlap with ASD genetic risk loci.Objectives: To estimate associations between DNA methylation in maternal blood, cord blood, and placenta and later diagnosis of ASD, and to evaluate enrichment of ASD-associated DNA methylation for known ASD-associated genes.Methods: In the Early Autism Risk Longitudinal Investigation (EARLI), an ASD-enriched risk birth cohort, genome-scale maternal blood (early n = 140 and late n = 75 pregnancy), infant cord blood (n = 133), and placenta (maternal n = 106 and fetal n = 107 compartments) DNA methylation was assessed on the Illumina 450k HumanMethylation array and compared to ASD diagnosis at 36 months of age. Differences in site-specific and global methylation were tested with ASD, as well as enrichment of single site associations for ASD risk genes (n = 881) from the Simons Foundation Autism Research Initiative (SFARI) database.Results: No individual DNA methylation site was associated with ASD at genome-wide significance, however, individual DNA methylation sites nominally associated with ASD (P < 0.05) in each tissue were highly enriched for SFARI genes (cord blood P = 7.9 × 10–29, maternal blood early pregnancy P = 6.1 × 10–27, maternal blood late pregnancy P = 2.8 × 10–16, maternal placenta P = 5.6 × 10–15, fetal placenta P = 1.3 × 10–20). DNA methylation sites nominally associated with ASD across all five tissues overlapped at 144 (29.5%) SFARI genes.Conclusion: DNA methylation sites nominally associated with later ASD diagnosis in multiple tissues were enriched for ASD risk genes. Our multi-tissue study demonstrates the utility of examining DNA methylation prior to ASD diagnosis.

scholarly journals Identification of CDH11 as an ASD risk gene by matched-gene co-expression analysis and mouse behavioral studies

2020 ◽  
Author(s):  
Nan Wu ◽  
Yue Wang ◽  
Yi-Hsuan Pan ◽  
Xiao-Bing Yuan
Keyword(s):  
Expression Analysis ◽  
Expression Profiles ◽  
Autism Spectrum ◽  
Molecular Pathways ◽  
Behavioral Alterations ◽  
High Confidence ◽  
Risk Genes ◽  
Risk Gene ◽  
Behavioral Studies ◽  
Mrna Length

AbstractIn the study of autism spectrum disorder (ASD) by gene co-expression analysis (GCA), we found that four gene features, including gene size, mRNA length, mRNA abundance, and guanine-cytosine content, profoundly affect gene co-expression profiles. To circumvent the potential interference of these confounding factors on GCA, we developed the “matched-gene co-expression analysis” (MGCA) to investigate gene co-expression relationships. This method demonstrated the convergent expression profile of high confidence ASD risk genes and effectively revealed convergent molecular pathways of ASD risk genes. Application of MGCA to two ASD candidate genes CDH11 and CDH9 showed association of CDH11, but not CDH9, with ASD. Mouse behavioral studies showed that Cdh11-null mice, but not Cdh9-null mice, have multiple autistic-like behavioral alterations. This study confirmed that CDH11 is an important ASD risk gene and demonstrated the importance of considering matched gene features in the analysis of gene co-expression.

scholarly journals Duplicated dnmt3aa and dnmt3ab DNA Methyltransferase Genes Play Essential and Non-Overlapped Functions on Modulating Behavioral Control in Zebrafish

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1322
Author(s):  
Yu-Heng Lai ◽  
Gilbert Audira ◽  
Sung-Tzu Liang ◽  
Petrus Siregar ◽  
Michael Edbert Suryanto ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Social Interaction ◽  
Dna Methyltransferase ◽  
Short Term Memory ◽  
De Novo ◽  
Behavioral Control ◽  
Methylation Pattern ◽  
Color Preference ◽  
Fear Response ◽  
Behavioral Alterations

DNA methylation plays several roles in regulating neuronal proliferation, differentiation, and physiological functions. The major de novo methyltransferase, DNMT3, controls the DNA methylation pattern in neurons according to environmental stimulations and behavioral regulations. Previous studies demonstrated that knockout of Dnmt3 induced mouse anxiety; however, controversial results showed that activation of Dnmt3 causes anxiolytic behavior. Thus, an alternative animal model to clarify Dnmt3 on modulating behavior is crucial. Therefore, we aimed to establish a zebrafish (Danio rerio) model to clarify the function of dnmt3 on fish behavior by behavioral endpoint analyses. We evaluated the behaviors of the wild type, dnmt3aa, and dnmt3ab knockout (KO) fish by the novel tank, mirror biting, predator avoidance, social interaction, shoaling, circadian rhythm locomotor activity, color preference, and short-term memory tests. The results indicated that the dnmt3aa KO fish possessed abnormal exploratory behaviors and less fear response to the predator. On the other hand, dnmt3ab KO fish displayed less aggression, fear response to the predator, and interests to interact with their conspecifics, loosen shoaling formation, and dysregulated color preference index ranking. Furthermore, both knockout fishes showed higher locomotion activity during the night cycle, which is a sign of anxiety. However, changes in some neurotransmitter levels were observed in the mutant fishes. Lastly, whole-genome DNA methylation sequencing demonstrates a potential network of Dnmt3a proteins that is responsive to behavioral alterations. To sum up, the results suggested that the dnmt3aa KO or dnmt3ab KO fish display anxiety symptoms, which supported the idea that Dnmt3 modulates the function involved in emotional control, social interaction, and cognition.

scholarly journals Sperm DNA methylation epimutation biomarker for paternal offspring autism susceptibility

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicolás Garrido ◽  
Fabio Cruz ◽  
Rocio Rivera Egea ◽  
Carlos Simon ◽  
Ingrid Sadler-Riggleman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Autism Spectrum ◽  
Epigenetic Alterations ◽  
Genome Wide ◽  
Sperm Dna ◽  
A Genome ◽  
Potential Biomarker ◽  
Test Sets ◽  
Autism Susceptibility ◽  
Sperm Dna Methylation

Abstract Background Autism spectrum disorder (ASD) has increased over tenfold over the past several decades and appears predominantly associated with paternal transmission. Although genetics is anticipated to be a component of ASD etiology, environmental epigenetics is now also thought to be an important factor. Epigenetic alterations, such as DNA methylation, have been correlated with ASD. The current study was designed to identify a DNA methylation signature in sperm as a potential biomarker to identify paternal offspring autism susceptibility. Methods and results Sperm samples were obtained from fathers that have children with or without autism, and the sperm then assessed for alterations in DNA methylation. A genome-wide analysis (> 90%) for differential DNA methylation regions (DMRs) was used to identify DMRs in the sperm of fathers (n = 13) with autistic children in comparison with those (n = 13) without ASD children. The 805 DMR genomic features such as chromosomal location, CpG density and length of the DMRs were characterized. Genes associated with the DMRs were identified and found to be linked to previously known ASD genes, as well as other neurobiology-related genes. The potential sperm DMR biomarkers/diagnostic was validated with blinded test sets (n = 8–10) of individuals with an approximately 90% accuracy. Conclusions Observations demonstrate a highly significant set of 805 DMRs in sperm that can potentially act as a biomarker for paternal offspring autism susceptibility. Ancestral or early-life paternal exposures that alter germline epigenetics are anticipated to be a molecular component of ASD etiology.

scholarly journals Association of CDH11 with Autism Spectrum Disorder Revealed by Matched-gene Co-expression Analysis and Mouse Behavioral Studies

2021 ◽  
Author(s):  
Nan Wu ◽  
Yue Wang ◽  
Jing-Yan Jia ◽  
Yi-Hsuan Pan ◽  
Xiao-Bing Yuan
Keyword(s):  
Autism Spectrum Disorder ◽  
Expression Analysis ◽  
Gene Prediction ◽  
Expression Profiles ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Developmental Expression ◽  
Behavioral Alterations ◽  
Risk Genes ◽  
Behavioral Studies

AbstractA large number of putative risk genes for autism spectrum disorder (ASD) have been reported. The functions of most of these susceptibility genes in developing brains remain unknown, and causal relationships between their variation and autism traits have not been established. The aim of this study was to predict putative risk genes at the whole-genome level based on the analysis of gene co-expression with a group of high-confidence ASD risk genes (hcASDs). The results showed that three gene features – gene size, mRNA abundance, and guanine-cytosine content – affect the genome-wide co-expression profiles of hcASDs. To circumvent the interference of these features in gene co-expression analysis, we developed a method to determine whether a gene is significantly co-expressed with hcASDs by statistically comparing the co-expression profile of this gene with hcASDs to that of this gene with permuted gene sets of feature-matched genes. This method is referred to as "matched-gene co-expression analysis" (MGCA). With MGCA, we demonstrated the convergence in developmental expression profiles of hcASDs and improved the efficacy of risk gene prediction. The results of analysis of two recently-reported ASD candidate genes, CDH11 and CDH9, suggested the involvement of CDH11, but not CDH9, in ASD. Consistent with this prediction, behavioral studies showed that Cdh11-null mice, but not Cdh9-null mice, have multiple autism-like behavioral alterations. This study highlights the power of MGCA in revealing ASD-associated genes and the potential role of CDH11 in ASD.

scholarly journals Integrative analysis of DNA methylation suggests down-regulation of oncogenic pathways and reduced de-novo mutation in survival outliers of glioblastoma

2018 ◽  
Author(s):  
Taeyoung Hwang ◽  
Dimitrios Mathios ◽  
Kerrie L McDonald ◽  
Irene Daris ◽  
Sung-Hye Park ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cancer Progression ◽  
De Novo ◽  
Cpg Islands ◽  
Methylation Pattern ◽  
De Novo Mutation ◽  
Cancer Type ◽  
De Novo Mutations ◽  
Dna Hypomethylation ◽  
A Genome

AbstractThe study of survival outliers of glioblastoma (GBM) can have important implications on gliomagenesis as well as in the identification of ways to alter clinical course on this almost uniformly lethal cancer type. However, current studied epigenetic and genetic signatures of the GBM outliers have failed to identify unifying criteria to characterize this unique group of patients. In this study, we profiled the global DNA methylation pattern of mainly IDH1 wild type survival outliers of glioblastoma and performed comprehensive enrichment analyses with genomic and epigenomic signatures. We found that the genome of long-term survivors in glioblastoma is differentially methylated relative to short-term survivor patients depending on CpG density: hypermethylation near CpG islands (CGIs) and hypomethylation far from CGIs. Interestingly, these two patterns are associated with distinct oncogenic aspects in gliomagenesis. The hypomethylation pattern at the region distant from CGI is associated with lower rates of de novo mutations while the hypermethylation at CGIs correlates with transcriptional downregulation of genes involved in cancer progression pathways. These results extend our understanding of DNA methylation of survival outliers in glioblastoma in a genome-wide level, and provide insight on the potential impact of DNA hypomethylation in cancer genome.

scholarly journals Genome-Wide DNA Methylation Analysis of a Cohort of 41 Patients Affected by Oculo-Auriculo-Vertebral Spectrum (OAVS)

2021 ◽  
Vol 22 (3) ◽  
pp. 1190
Author(s):  
Valentina Guida ◽  
Luciano Calzari ◽  
Maria Teresa Fadda ◽  
Francesca Piceci-Sparascio ◽  
Maria Cristina Digilio ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Branchial Arch ◽  
Methylation Pattern ◽  
Abnormal Development ◽  
Epigenetic Mechanisms ◽  
Alternative Analysis ◽  
Chromatin Dynamics ◽  
Genome Wide ◽  
A Genome ◽  
Ear Anomalies

Oculo-auriculo-vertebral-spectrum (OAVS; OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. MYT1, AMIGO2, and ZYG11B gene variants were reported in a few OAVS patients, but the etiology remains largely unknown. A multifactorial origin has been proposed, including the involvement of environmental and epigenetic mechanisms. To identify the epigenetic mechanisms contributing to OAVS, we evaluated the DNA-methylation profiles of 41 OAVS unrelated affected individuals by using a genome-wide microarray-based methylation approach. The analysis was first carried out comparing OAVS patients with controls at the group level. It revealed a moderate epigenetic variation in a large number of genes implicated in basic chromatin dynamics such as DNA packaging and protein-DNA organization. The alternative analysis in individual profiles based on the searching for Stochastic Epigenetic Variants (SEV) identified an increased number of SEVs in OAVS patients compared to controls. Although no recurrent deregulated enriched regions were found, isolated patients harboring suggestive epigenetic deregulations were identified. The recognition of a different DNA methylation pattern in the OAVS cohort and the identification of isolated patients with suggestive epigenetic variations provide consistent evidence for the contribution of epigenetic mechanisms to the etiology of this complex and heterogeneous disorder.

scholarly journals DNA Methylation Levels of Melanoma Risk Genes Are Associated with Clinical Characteristics of Melanoma Patients

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Érica S. S. de Araújo ◽  
Dimitrius T. Pramio ◽  
André Y. Kashiwabara ◽  
Paula C. Pennacchi ◽  
Silvya S. Maria-Engler ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Clinical Characteristics ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Methylation Pattern ◽  
Risk Genes ◽  
Mutation Status ◽  
Melanoma Patients ◽  
Status Number

In melanoma development, oncogenic process is mediated by genetic and epigenetic mutations, and few studies have so far explored the role of DNA methylation either as predisposition factor or biomarker. We tested patient samples for germlineCDKN2Amethylation status and found no evidence of inactivation by promoter hypermethylation. We have also investigated the association of clinical characteristics of samples with the DNA methylation pattern of twelve genes relevant for melanomagenesis. Five genes (BAP1, MGMT, MITF, PALB2, andPOT1) presented statistical association between blood DNA methylation levels and eitherCDKN2A-mutation status, number of lesions, or Breslow thickness. In tumors, five genes (KIT, MGMT, MITF, TERT, andTNF) exhibited methylation levels significantly different between tumor groups including acral compared to nonacral melanomas and matched primary lesions and metastases. Our data pinpoint that the methylation level of eight melanoma-associated genes could potentially represent markers for this disease both in peripheral blood and in tumor samples.

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