CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder
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 hav...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-01-01
|
| Series: | Frontiers in Psychiatry |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1078894/full |
| _version_ | 1797948188205776896 |
|---|---|
| author | Sheila T. Nagamatsu Sheila T. Nagamatsu Sheila T. Nagamatsu Gregory Rompala Yasmin L. Hurd Diana L. Núñez-Rios Diana L. Núñez-Rios Diana L. Núñez-Rios Janitza L. Montalvo-Ortiz Janitza L. Montalvo-Ortiz Janitza L. Montalvo-Ortiz Traumatic Stress Brain Research Group Victor E. Alvarez David Benedek Alicia Che Dianne A. Cruz David A. Davis Matthew J. Girgenti Ellen Hoffman Paul E. Holtzheimer Bertrand R. Huber Alfred Kaye John H. Krystal Adam T. Labadorf Terence M. Keane Mark W. Logue Ann McKee Brian Marx Deborah Mash Mark W. Miller Crystal Noller JM-O William K. Scott Paula Schnurr Thor Stein Robert Ursano Douglas E. Williamson Erika J. Wolf Keith A. Young |
| author_facet | Sheila T. Nagamatsu Sheila T. Nagamatsu Sheila T. Nagamatsu Gregory Rompala Yasmin L. Hurd Diana L. Núñez-Rios Diana L. Núñez-Rios Diana L. Núñez-Rios Janitza L. Montalvo-Ortiz Janitza L. Montalvo-Ortiz Janitza L. Montalvo-Ortiz Traumatic Stress Brain Research Group Victor E. Alvarez David Benedek Alicia Che Dianne A. Cruz David A. Davis Matthew J. Girgenti Ellen Hoffman Paul E. Holtzheimer Bertrand R. Huber Alfred Kaye John H. Krystal Adam T. Labadorf Terence M. Keane Mark W. Logue Ann McKee Brian Marx Deborah Mash Mark W. Miller Crystal Noller JM-O William K. Scott Paula Schnurr Thor Stein Robert Ursano Douglas E. Williamson Erika J. Wolf Keith A. Young |
| author_sort | Sheila T. Nagamatsu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T21:40:30Z |
| format | Article |
| id | doaj.art-8e534560e2b9492589d5919efc931441 |
| institution | Directory Open Access Journal |
| issn | 1664-0640 |
| language | English |
| last_indexed | 2024-04-10T21:40:30Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Psychiatry |
| spelling | doaj.art-8e534560e2b9492589d5919efc9314412023-01-19T06:11:18ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402023-01-011310.3389/fpsyt.2022.10788941078894CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorderSheila T. Nagamatsu0Sheila T. Nagamatsu1Sheila T. Nagamatsu2Gregory Rompala3Yasmin L. Hurd4Diana L. Núñez-Rios5Diana L. Núñez-Rios6Diana L. Núñez-Rios7Janitza L. Montalvo-Ortiz8Janitza L. Montalvo-Ortiz9Janitza L. Montalvo-Ortiz10Traumatic Stress Brain Research GroupVictor E. AlvarezDavid BenedekAlicia CheDianne A. CruzDavid A. DavisMatthew J. GirgentiEllen HoffmanPaul E. HoltzheimerBertrand R. HuberAlfred KayeJohn H. KrystalAdam T. LabadorfTerence M. KeaneMark W. LogueAnn McKeeBrian MarxDeborah MashMark W. MillerCrystal Noller JM-OWilliam K. ScottPaula SchnurrThor SteinRobert UrsanoDouglas E. WilliamsonErika J. WolfKeith A. YoungDivision of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United StatesVA Connecticut (VA CT) Healthcare Center, West Haven, CT, United StatesClinical Neurosciences Division, U.S. Department of Veterans Affairs National Center of Posttraumatic Stress Disorder, West Haven, CT, United StatesIcahn School of Medicine at Mount Sinai, New York, NY, United StatesIcahn School of Medicine at Mount Sinai, New York, NY, United StatesDivision of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United StatesVA Connecticut (VA CT) Healthcare Center, West Haven, CT, United StatesClinical Neurosciences Division, U.S. Department of Veterans Affairs National Center of Posttraumatic Stress Disorder, West Haven, CT, United StatesDivision of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United StatesVA Connecticut (VA CT) Healthcare Center, West Haven, CT, United StatesClinical Neurosciences Division, U.S. Department of Veterans Affairs National Center of Posttraumatic Stress Disorder, West Haven, CT, United StatesIntroductionDNA 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.https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1078894/fullopioidmethylationnon-CpG sitepostmortem human brainorbitofrontal cortexepigenetic |
| spellingShingle | Sheila T. Nagamatsu Sheila T. Nagamatsu Sheila T. Nagamatsu Gregory Rompala Yasmin L. Hurd Diana L. Núñez-Rios Diana L. Núñez-Rios Diana L. Núñez-Rios Janitza L. Montalvo-Ortiz Janitza L. Montalvo-Ortiz Janitza L. Montalvo-Ortiz Traumatic Stress Brain Research Group Victor E. Alvarez David Benedek Alicia Che Dianne A. Cruz David A. Davis Matthew J. Girgenti Ellen Hoffman Paul E. Holtzheimer Bertrand R. Huber Alfred Kaye John H. Krystal Adam T. Labadorf Terence M. Keane Mark W. Logue Ann McKee Brian Marx Deborah Mash Mark W. Miller Crystal Noller JM-O William K. Scott Paula Schnurr Thor Stein Robert Ursano Douglas E. Williamson Erika J. Wolf Keith A. Young CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder Frontiers in Psychiatry opioid methylation non-CpG site postmortem human brain orbitofrontal cortex epigenetic |
| title | CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder |
| title_full | CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder |
| title_fullStr | CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder |
| title_full_unstemmed | CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder |
| title_short | CpH methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder |
| title_sort | cph methylome analysis in human cortical neurons identifies novel gene pathways and drug targets for opioid use disorder |
| topic | opioid methylation non-CpG site postmortem human brain orbitofrontal cortex epigenetic |
| url | https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1078894/full |
| work_keys_str_mv | AT sheilatnagamatsu cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT sheilatnagamatsu cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT sheilatnagamatsu cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT gregoryrompala cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT yasminlhurd cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT dianalnunezrios cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT dianalnunezrios cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT dianalnunezrios cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT janitzalmontalvoortiz cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT janitzalmontalvoortiz cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT janitzalmontalvoortiz cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT traumaticstressbrainresearchgroup cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT victorealvarez cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT davidbenedek cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT aliciache cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT dianneacruz cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT davidadavis cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT matthewjgirgenti cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT ellenhoffman cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT pauleholtzheimer cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT bertrandrhuber cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT alfredkaye cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT johnhkrystal cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT adamtlabadorf cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT terencemkeane cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT markwlogue cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT annmckee cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT brianmarx cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT deborahmash cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT markwmiller cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT crystalnoller cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT jmo cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT williamkscott cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT paulaschnurr cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT thorstein cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT robertursano cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT douglasewilliamson cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT erikajwolf cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder AT keithayoung cphmethylomeanalysisinhumancorticalneuronsidentifiesnovelgenepathwaysanddrugtargetsforopioidusedisorder |