Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study

Abstract DNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study MARBLES (Markers of Autism Risk in Babies—Learning Early Signs) of high-risk pregnancies. A total of 400 differentially methylated regions (DMRs) discriminated placentas stored from children later diagnosed with ASD compared to typically developing controls. These ASD DMRs were significantly enriched at promoters, mapped to 596 genes functionally enriched in neuronal development, and overlapped genetic ASD risk. ASD DMRs at CYP2E1 and IRS2 reached genome-wide significance, replicated by pyrosequencing and correlated with expression differences in brain. Methylation at CYP2E1 associated with both ASD diagnosis and genotype within the DMR. In contrast, methylation at IRS2 was unaffected by within DMR genotype but modified by preconceptional maternal prenatal vitamin use. This study therefore identified two potentially useful early epigenetic markers for ASD in placenta.

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Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study

10.1101/501007 ◽

2018 ◽

Cited By ~ 2

Author(s):

Yihui Zhu ◽

Charles E. Mordaunt ◽

Dag H. Yasui ◽

Ria Marathe ◽

Rochelle L. Coulson ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Dna Methylation ◽

Neuronal Development ◽

Autism Spectrum ◽

Child Outcome ◽

Genome Wide ◽

Genetic And Environmental Factors ◽

A Prospective Study ◽

Methylation Patterns ◽

Genome Wide Significance

AbstractDNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study of high-risk pregnancies. 400 differentially methylated regions (DMRs) discriminated placentas stored from children later diagnosed with ASD compared to typical controls. These ASD DMRs were significantly enriched at promoters, mapped to 596 genes functionally enriched in neuronal development, and overlapped genetic ASD risk. ASD DMRs at CYP2E1 and IRS2 reached genome-wide significance, replicated by pyrosequencing, and correlated with expression. Methylation at CYP2E1 associated with both ASD diagnosis and cis genotype, while methylation at IRS2 was unaffected by cis genotype but modified by preconceptional maternal prenatal vitamin use. This study therefore identified two potentially useful early epigenetic markers for ASD in placenta.

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Genome-wide molecular effects of the neuropsychiatric 16p11 CNVs in an iPSC-to-iN neuronal model

10.1101/2020.02.09.940965 ◽

2020 ◽

Author(s):

Thomas R. Ward ◽

Xianglong Zhang ◽

Louis C. Leung ◽

Bo Zhou ◽

Kristin Muench ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Cell Model ◽

Copy Number Variants ◽

Induced Pluripotent Stem Cell ◽

Neuronal Model ◽

Autism Spectrum ◽

Genome Wide ◽

Induced Pluripotent ◽

Methylation Patterns

AbstractCopy number variants (CNVs), either deletions or duplications, at the 16p11.2 locus in the human genome are known to increase the risk for autism spectrum disorders (ASD), schizophrenia, and for several other developmental conditions. Here, we investigate the global effects on gene expression and DNA methylation using a 16p11.2 CNV patient-derived induced pluripotent stem cell (iPSC) to induced neuron (iN) cell model system. This approach revealed genome-wide and cell-type specific alterations to both gene expression and DNA methylation patterns and also yielded specific leads on genes potentially contributing to some of the known 16p11.2 patient phenotypes. PCSK9 is identified as a possible contributing factor to the symptoms seen in carriers of the 16p11.2 CNVs. The protocadherin (PCDH) gene family is found to have altered DNA methylation patterns in the CNV patient samples. The iPSC lines used for this study are available through a repository as a resource for research into the molecular etiology of the clinical phenotypes of 16p11.2 CNVs and into that of neuropsychiatric and neurodevelopmental disorders in general.

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MOSAIC EPIGENETIC DYSREGULATION OF ECTODERMAL CELLS IN AUTISM SPECTRUM DISORDER

10.1101/004853 ◽

2014 ◽

Author(s):

Esther R. Berko ◽

Masako Suzuki ◽

Faygel Beren ◽

Christophe Lemetre ◽

Christine M. Alaimo ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Dna Methylation ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Dna Mutations ◽

Genome Wide ◽

Methylation Assay ◽

Increased Risk ◽

Methylation Patterns ◽

Encoding Protein

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested an homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

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Genome-wide DNA methylation patterns in Autism Spectrum Disorder and mitochondrial function

10.1101/310748 ◽

2018 ◽

Cited By ~ 1

Author(s):

Sofia Stathopoulos ◽

Renaud Gaujoux ◽

Colleen O’Ryan

Keyword(s):

Autism Spectrum Disorder ◽

Dna Methylation ◽

Brain Tissue ◽

Mitochondrial Function ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Protein Ubiquitination ◽

Genome Wide ◽

Differentially Methylated Genes ◽

Methylation Patterns

AbstractAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by phenotypic heterogeneity and overlapping co-morbidities. The genetic architecture of ASD is complex, with 100’s of risk genes cumulatively contributing to the aetiology of ASD. Epigenetic mechanisms, particularly DNA methylation, have been associated with ASD. The vast majority of ASD molecular research has focused on Northern European populations, with a paucity of data from Africa. This study examines genome-wide DNA methylation patterns in a novel cohort of South African children with ASD and matched, unrelated controls. We performed a whole-genome DNA methylation screen using the Illumina 450K Human Methylation Array. We identify differentially methylated loci associated with ASD across 898 genes (p-value ≤ 0.05). Using a pathway analysis framework, we find nine enriched canonical pathways implicating 32 of the significant genes in our ASD cohort. These pathways converge on two crucial biological processes: mitochondrial metabolism and protein ubiquitination, both hallmarks of mitochondrial function. The involvement of mitochondrial function in ASD aetiology is in line with the recently reported transcriptomic dysregulation associated with the disorder. The differentially methylated genes in our cohort overlap with the gene co-expression modules identified in brain tissue from five major neurological disorders, including ASD. We find significant enrichment of three gene modules, two of which are classified as Mitochondrial and were significantly downregulated in ASD brains. Furthermore, we find significant overlap between differentially methylated and differentially expressed genes from our dataset with a RNA seq dataset from ASD brain tissue. This overlap is particularly significant across the Occipital brain region (padj= 0.0002) which has known association to ASD. Our differential methylation data recapitulate the expression differences of genes and co-expression module functions observed in ASD brain tissue which is consistent with a central role for DNA-methylation leading to mitochondrial dysfunction in the aetiology of ASD.

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Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

Communications Biology ◽

10.1038/s42003-021-02179-x ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Todd R. Robeck ◽

Zhe Fei ◽

Ake T. Lu ◽

Amin Haghani ◽

Eve Jourdain ◽

...

Keyword(s):

Dna Methylation ◽

Age Estimation ◽

Species Conservation ◽

Genome Wide ◽

Epigenetic Aging ◽

Highly Correlated ◽

Methylation Patterns ◽

Cg Dinucleotides ◽

Free Ranging ◽

Unique Species

AbstractThe development of a precise blood or skin tissue DNA Epigenetic Aging Clock for Odontocete (OEAC) would solve current age estimation inaccuracies for wild odontocetes. Therefore, we determined genome-wide DNA methylation profiles using a custom array (HorvathMammalMethyl40) across skin and blood samples (n = 446) from known age animals representing nine odontocete species within 4 phylogenetic families to identify age associated CG dinucleotides (CpGs). The top CpGs were used to create a cross-validated OEAC clock which was highly correlated for individuals (r = 0.94) and for unique species (median r = 0.93). Finally, we applied the OEAC for estimating the age and sex of 22 wild Norwegian killer whales. DNA methylation patterns of age associated CpGs are highly conserved across odontocetes. These similarities allowed us to develop an odontocete epigenetic aging clock (OEAC) which can be used for species conservation efforts by provide a mechanism for estimating the age of free ranging odontocetes from either blood or skin samples.

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Aging-associated distinctive DNA methylation changes of LINE-1 retrotransposons in pure cell-free DNA from human blood

Scientific Reports ◽

10.1038/s41598-020-79126-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Wardah Mahmood ◽

Lars Erichsen ◽

Pauline Ott ◽

Wolfgang A. Schulz ◽

Johannes C. Fischer ◽

...

Keyword(s):

Dna Methylation ◽

Cell Free Dna ◽

The Past ◽

Free Dna ◽

Genome Wide ◽

Cancerous Cell ◽

Pure Cell ◽

Epigenetic Biomarker ◽

Methylation Patterns ◽

Cancerous Cells

AbstractLINE-1 hypomethylation of cell-free DNA has been described as an epigenetic biomarker of human aging. However, in the past, insufficient differentiation between cellular and cell-free DNA may have confounded analyses of genome-wide methylation levels in aging cells. Here we present a new methodological strategy to properly and unambiguously extract DNA methylation patterns of repetitive, as well as single genetic loci from pure cell-free DNA from peripheral blood. Since this nucleic acid fraction originates mainly in apoptotic, senescent and cancerous cells, this approach allows efficient analysis of aged and cancerous cell-specific DNA methylation patterns for diagnostic and prognostic purposes. Using this methodology, we observe a significant age-associated erosion of LINE-1 methylation in cfDNA suggesting that the threshold of hypomethylation sufficient for relevant LINE-1 activation and consequential harmful retrotransposition might be reached at higher age. We speculate that this process might contribute to making aging the main risk factor for many cancers.

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Genome-Wide DNA Methylation Patterns Analysis of Noncoding RNAs in Temporal Lobe Epilepsy Patients

Molecular Neurobiology ◽

10.1007/s12035-016-0353-x ◽

2017 ◽

Vol 55 (1) ◽

pp. 793-803 ◽

Cited By ~ 13

Author(s):

Wenbiao Xiao ◽

Yuze Cao ◽

Hongyu Long ◽

Zhaohui Luo ◽

Shuyu Li ◽

...

Keyword(s):

Dna Methylation ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Noncoding Rnas ◽

Genome Wide ◽

Methylation Patterns

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Abstract 40: Disturbed Flow Alters Genomewide DNA Methylation Patterns, Regulating Endothelial Gene Expression and Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.40 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Jessilyn Dunn ◽

Haiwei Qiu ◽

Soyeon Kim ◽

Daudi Jjingo ◽

Ryan Hoffman ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Dna Methyltransferase ◽

Methylation Status ◽

Western Diet ◽

Dependent Manner ◽

Gene Promoters ◽

Genome Wide ◽

Methylation Patterns ◽

Endothelial Gene Expression

Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow (d-flow), which alters gene expression, endothelial function, and atherosclerosis. Here, we show that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase (DNMT)-dependent manner. We found that d-flow induced expression of DNMT1, but not DNMT3a or DNMT3b, in mouse arterial endothelium in vivo and in cultured endothelial cells by oscillatory shear (OS) compared to unidirectional laminar shear in vitro. The DNMT inhibitor 5-Aza-2’deoxycytidine (5Aza) or DNMT1 siRNA significantly reduced OS-induced endothelial inflammation. Moreover, 5Aza reduced lesion formation in two atherosclerosis models using ApoE-/- mice (western diet for 3 months and the partial carotid ligation model with western diet for 3 weeks). To identify the 5Aza mechanisms, we conducted two genome-wide studies: reduced representation bisulfite sequencing (RRBS) and transcript microarray using endothelial-enriched gDNA and RNA, respectively, obtained from the partially-ligated left common carotid artery (LCA exposed to d-flow) and the right contralateral control (RCA exposed to s-flow) of mice treated with 5Aza or vehicle. D-flow induced DNA hypermethylation in 421 gene promoters, which was significantly prevented by 5Aza in 335 genes. Systems biological analyses using the RRBS and the transcriptome data revealed 11 mechanosensitive genes whose promoters were hypermethylated by d-flow but rescued by 5Aza treatment. Of those, five genes contain hypermethylated cAMP-response-elements in their promoters, including the transcription factors HoxA5 and Klf3. Their methylation status could serve as a mechanosensitive master switch in endothelial gene expression. Our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.

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Genome-wide DNA methylation patterns in coronary heart disease

Herz ◽

10.1007/s00059-017-4616-8 ◽

2017 ◽

Vol 43 (7) ◽

pp. 656-662 ◽

Cited By ~ 3

Author(s):

X. Wang ◽

A.-H. Liu ◽

Z.-W. Jia ◽

K. Pu ◽

K.-Y. Chen ◽

...

Keyword(s):

Dna Methylation ◽

Coronary Heart Disease ◽

Heart Disease ◽

Genome Wide ◽

Methylation Patterns

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Intergenerational epigenetic inheritance in reef-building corals

10.1101/269076 ◽

2018 ◽

Cited By ~ 6

Author(s):

Yi Jin Liew ◽

Emily J. Howells ◽

Xin Wang ◽

Craig T. Michell ◽

John A. Burt ◽

...

Keyword(s):

Dna Methylation ◽

Intergenerational Transmission ◽

Epigenetic Inheritance ◽

Cpg Methylation ◽

Epigenetic Mechanisms ◽

Transgenerational Inheritance ◽

Genome Wide ◽

Methylation Patterns ◽

Hypermethylated Genes

MainThe notion that intergenerational or transgenerational inheritance operates solely through genetic means is slowly being eroded: epigenetic mechanisms have been shown to induce heritable changes in gene activity in plants1,2and metazoans1,3. Inheritance of DNA methylation provides a potential pathway for environmentally induced phenotypes to contribute to evolution of species and populations1–4. However, in basal metazoans, it is unknown whether inheritance of CpG methylation patterns occurs across the genome (as in plants) or as rare exceptions (as in mammals)4. Here, we demonstrate genome-wide intergenerational transmission of CpG methylation patterns from parents to sperm and larvae in a reef-building coral. We also show variation in hypermethylated genes in corals from distinct environments, indicative of responses to variations in temperature and salinity. These findings support a role of DNA methylation in the transgenerational inheritance of traits in corals, which may extend to enhancing their capacity to adapt to climate change.

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