Effect of Prenatal Opioid Exposure on the Human Placental Methylome

Borrelli, Kristyn N.; Wachman, Elisha M.; Beierle, Jacob A; Taglauer, Elizabeth; Jain, Mayuri; Bryant, Camron D.; Zhang, Huiping

doi:10.3390/biomedicines10051150

Cited by 10 publications

(2 citation statements)

References 64 publications

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“…DNAm generally occurs in cytosine-guanine dinucleotides linked by a phosphate group (CpG site) and is associated with gene repression when located in the CpG island of the promoter region ( 5 ). Our group and others have identified differentially methylated CpG sites associated with OUD in studies examining peripheral tissue ( 6 – 8 ).…”

Section: Introductionmentioning

confidence: 85%

CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder

Nagamatsu

Rompala²,

Hurd³

et al. 2023

Front. Psychiatry

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IntroductionDNA methylation (DNAm), an epigenetic mechanism, has been associated with opioid use disorder (OUD) in preclinical and human studies. However, most of the studies have focused on DNAm at CpG sites. DNAm at non-CpG sites (mCpHs, where H indicates A, T, or C) has been recently shown to have a role in gene regulation and to be highly abundant in neurons. However, its role in OUD is unknown. This work aims to evaluate mCpHs in the human postmortem orbital frontal cortex (OFC) in the context of OUD.MethodsA total of 38 Postmortem OFC samples were obtained from the VA Brain Bank (OUD = 12; Control = 26). mCpHs were assessed using reduced representation oxidative bisulfite sequencing in neuronal nuclei. Differential analysis was performed using the “methylkit” R package. Age, ancestry, postmortem interval, PTSD, and smoking status were included as covariates. Significant mCpHs were set at q-value < 0.05. Gene Ontology (GO) and KEGG enrichment analyses were performed for the annotated genes of all differential mCpH loci using String, ShinyGO, and amiGO software. Further, all annotated genes were analyzed using the Drug gene interaction database (DGIdb).ResultsA total of 2,352 differentially methylated genome-wide significant mCpHs were identified in OUD, mapping to 2,081 genes. GO analysis of genes with differential mCpH loci showed enrichment for nervous system development (p-value = 2.32E-19). KEGG enrichment analysis identified axon guidance and glutamatergic synapse (FDR 9E-4–2.1E-2). Drug interaction analysis found 3,420 interactions between the annotated genes and drugs, identifying interactions with 15 opioid-related drugs, including lofexidine and tizanidine, both previously used for the treatment of OUD-related symptoms.ConclusionOur findings suggest a role of mCpHs for OUD in cortical neurons and reveal important biological pathways and drug targets associated with the disorder.

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Section: Introductionmentioning

confidence: 85%

CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder

Nagamatsu

Rompala²,

Hurd³

et al. 2023

Front. Psychiatry

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“…However, an FDR adjustment assumes independence in the comparisons, and DNA methylation levels across the genome are not independent. Thus, several studies have taken an approach that requires a larger effect size (i.e., > 10%) with a more liberal p value cut-off [78][79][80][81] . Therefore, to detect intervention-sensitive DML, we established as cutoff a p value ≤ 0.001 combined with an average difference in methylation between T1 and T2 greater than 10%.…”

Section: Identification Of Differentially Methylated Loci (Dml)mentioning

confidence: 99%

Epigenetic impact of a 1-week intensive multimodal group program for adolescents with multiple adverse childhood experiences

Kaliman

Cosín-Tomás²,

Madrid³

et al. 2022

Sci Rep

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Adverse childhood experiences (ACEs, i.e., abuse, neglect, household dysfunction) represent a potential risk factor for a wide range of long-lasting diseases and shorter life expectancy. We recently described a 1-week residential group program, based on mindfulness training, artistic expression and EMDR group therapy, that significantly reduced PTSD-related symptoms and increased attention/awareness-related outcomes in adolescent girls with multiple ACEs in a randomized controlled study. Since epigenetic mechanisms (i.e., DNA methylation) have been associated with the long-lasting effects of ACEs, the present report extends these prior findings by exploring genome-wide DNA methylation changes following the program. Saliva samples from all participants (n = 44) were collected and genomic DNA was extracted prior (T1) and following (T2) the intervention. Genome-wide DNA methylation analysis using the MethylationEPIC beadchip array (Illumina) revealed 49 differentially methylated loci (DML; p value < 0.001; methylation change > 10%) that were annotated to genes with roles in biological processes linked to early childhood adversity (i.e., neural, immune, and endocrine pathways, cancer and cardiovascular disease). DNA sequences flanking these DML showed significant enrichment of transcription factor binding sites involved in inflammation, cancer, cardiovascular disease, and brain development. Methylation changes in SIRT5 and TRAPPC2L genes showed associations with changes in trauma-related psychological measures. Results presented here suggest that this multimodal group program for adolescents with multiple victimization modulates the DNA methylome at sites of potential relevance for health and behavioral disorders associated with ACEs.

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Decreased myelin-related gene expression in the nucleus accumbens during spontaneous neonatal opioid withdrawal in the absence of long-term behavioral effects in adult outbred CFW mice

Borrelli,

Wingfield,

Yao

et al. 2023

Neuropharmacology

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Effect of Prenatal Opioid Exposure on the Human Placental Methylome

Cited by 10 publications

References 64 publications

CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder

CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder

Epigenetic impact of a 1-week intensive multimodal group program for adolescents with multiple adverse childhood experiences

Decreased myelin-related gene expression in the nucleus accumbens during spontaneous neonatal opioid withdrawal in the absence of long-term behavioral effects in adult outbred CFW mice

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