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

Zhu, Yihui; Mordaunt, Charles E.; Yasui, Dag H.; Marathe, Ria; Coulson, Rochelle L.; Dunaway, Keith W.; Walker, Cheryl K.; Ozonoff, Sally J; Hertz‐Picciotto, Irva; Schmidt, Rebecca J.; LaSalle, Janine M.

doi:10.1101/501007

Cited by 12 publications

(15 citation statements)

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“…To test the hypothesis that cord blood ASD DMRs were reflecting chromatin differences in cis -regulatory regions important in early prenatal life, we examined the enrichment of autosomal and X chromosomal DMRs for histone PTMs and chromatin states across many tissues and stages. Cord blood ASD DMRs were positionally compared with histone PTM chromatin immunoprecipitation sequencing (ChIP-seq) peaks and ChromHMM-defined chromatin states in 127 cell types from the Roadmap Epigenomics Project [ 30 ]. ASD hyper- and hypomethylated DMRs in males and females in both sample sets were enriched for chromatin states involved in transcriptional regulation, including active transcription start sites (TssA and TssAFlnk) and bivalent enhancers (EnhBiv), across tissue types ( q < 0.05; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For both discovery and replication sets, enrichment of sex-stratified ASD DMR genes with those identified in previous genomic, epigenomic, and transcriptional studies of ASD was examined. Gene lists were sourced from the reported hits of each paper [7,13,[22][23][24][25][26][27][28][29][30][31]. Reported regions from epigenomic studies were converted to the hg38 assembly using the liftOver() function from the rtracklayer R package (v1.42.2, [90]), and genes were annotated using the same approach used in GREAT [62].…”

Section: Autism Gene Enrichmentmentioning

confidence: 99%

“…Similarities in brain epigenetic dysregulation have been found between individuals with idiopathic and syndromic ASDs, including Dup15q and Rett syndrome [24,26,27]. Tissues easily accessible in humans, such as placenta, paternal sperm, buccal, and blood, have been used to identify differential methylation in ASD by EWAS [28][29][30][31][32], but few individual loci have been replicated. Previous EWAS have been hampered by study design limitations, including case-control cohorts that may be confounded by reverse causation and microarray-based platforms that cover less than 3% of the CpG sites in the genome [33].…”

Section: Introductionmentioning

confidence: 99%

“…Previous EWAS have been hampered by study design limitations, including case-control cohorts that may be confounded by reverse causation and microarray-based platforms that cover less than 3% of the CpG sites in the genome [33]. Notably, a previous study from our group applied whole-genome bisulfite sequencing (WGBS) to prospectively collected placenta samples and identified significant differential methylation associated with ASD at CYP2E1 and IRS2 [30].…”

Section: Introductionmentioning

confidence: 99%

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Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

et al. 2020

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Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. The neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development and influence future health outcomes. Methods We performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. Samples were split into discovery and replication sets and stratified by sex, and their DNA methylation profiles were tested for differentially methylated regions (DMRs) between ASD and typically developing control cord blood samples. DMRs were mapped to genes and assessed for enrichment in gene function, tissue expression, chromosome location, and overlap with prior ASD studies. DMR coordinates were tested for enrichment in chromatin states and transcription factor binding motifs. Results were compared between discovery and replication sets and between males and females. Results We identified DMRs stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development. Conclusions At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD and provides novel insights for early diagnosis and therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Autism Gene Enrichmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

et al. 2020

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“…One of the most long‐standing cohorts is the Markers of Autism Risk in Babies Learning Early Signs (MARBLES). A prospective study of high‐risk pregnancies as part of this cohort reveals that 400 differentially methylated regions (DMR) distinguish placentas from offspring later diagnosed with ASD relative to those not diagnosed with such disorders (Zhu et al, 2019). DMR in CYP2E1 and IRS2 from placenta of autistic children reach genome‐wide significance with methylation at CYP2E1 positively correlating with ASD diagnosis and genotype within the DMR.…”

Section: Introductionmentioning

confidence: 99%

The placenta‐brain‐axis

Rosenfeld

2020

J of Neuroscience Research

135

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All mammalian species depend on the placenta, a transient organ, for exchange of gases, nutrients, and waste between the mother and conceptus. Besides serving as a conduit for such exchanges, the placenta produces hormones and other factors that influence maternal physiology and fetal development. To meet all of these adaptations, the placenta has evolved to become the most structurally diverse organ within all mammalian taxa. However, commonalities exist as to how placental responses promote survival against in utero threats and can alter the trajectory of fetal development, in particular the brain. Increasing evidence suggests that reactions of the placenta to various in utero stressors may lead to long‐standing health outcomes, otherwise considered developmental origin of health and disease effects. Besides transferring nutrients and gases, the placenta produces neurotransmitters, including serotonin, dopamine, norepinephrine/epinephrine, that may circulate and influence brain development. Neurobehavioral disorders, such as autism spectrum disorders, likely trace their origins back to placental disturbances. This intimate relationship between the placenta and brain has led to coinage of the term, the placenta‐brain‐axis. This axis will be the focus herein, including how conceptus sex might influence it, and technologies employed to parse out the effects of placental‐specific transcript expression changes on later neurobehavioral disorders. Ultimately, the placenta might provide a historical record of in utero threats the fetus confronted and a roadmap to understand how placenta responses to such encounters impacts the placental‐brain‐axis. Improved early diagnostic and preventative approaches may thereby be designed to mitigate such placental disruptions.

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Prenatal epigenetic factors are predisposing for neurodevelopmental disorders—Considering placenta as a model

Durbagula

Korlimarla

Ravikumar

et al. 2022

Birth Defects Research

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The heterogeneous characteristics of neurodevelopmental disorders (NDDs) have resulted in varied perspectives on their causation. The biology behind the phenotypic heterogeneity in NDDs is not yet well‐defined, but a strong genetic basis has become well accepted as causal for NDDs. Alongside this, there is growing focus on epigenetic mechanisms. The evidence mounting for in‐utero origins of NDDs has promoted research focused on epigenetic mechanisms that impact genes that program early brain development. Considering that placenta is a vital organ, this review emphasizes the prenatal factors and their effects on epigenetic changes influencing the normal functioning of the placenta, and factors mediating pathology in the developing fetus. Overall, it is an attempt to bring focus on the hypothesis that “Prenatal epigenetic factors in the placenta could be predisposing to NDDs (with special interest on autism spectrum disorders).” This review finds growing evidence for epigenetic modifications in the placenta that affect glucocorticoid, nutrient, and immune signaling pathways, eventually impacting fetal brain development. This evidence largely comes from animal models. Given the multicellular nature of placenta, we conclude that, there is a need for placental research focused on employing single‐cell approaches and genome‐wide methylation profiles to bring insights into specific molecular pathways in the placenta that regulate early brain development.

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

Cited by 12 publications

References 146 publications

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

The placenta‐brain‐axis

Prenatal epigenetic factors are predisposing for neurodevelopmental disorders—Considering placenta as a model

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