DNA Methylation Associated with Mitochondrial Dysfunction in a South African Autism Spectrum Disorder Cohort / Sofia STATHOPOULOS in Autism Research, 13-7 (July 2020)  

Public ISBD [article]  inAutism Research > 13-7 (July 2020) . - p.1079-1093 Titre : DNA Methylation Associated with Mitochondrial Dysfunction in a South African Autism Spectrum Disorder Cohort Type de document : Texte imprimé et/ou numérique Auteurs : Sofia STATHOPOULOS, Auteur ; Renaud GAUJOUX, Auteur ; Zander LINDEQUE, Auteur ; Caitlyn MAHONY, Auteur ; Rachelle VAN DER COLFF, Auteur ; Francois VAN DER WESTHUIZEN, Auteur ; Colleen O'RYAN, Auteur Article en page(s) : p.1079-1093 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder  DNA methylation  Pccb  Pcdha12  epigenetics  metabolomic profiles  mitochondrial dysfunction  organic acids Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is characterized by phenotypic heterogeneity and a complex genetic architecture which includes distinctive epigenetic patterns. We report differential DNA methylation patterns associated with ASD in South African children. An exploratory whole-epigenome methylation screen using the Illumina 450?K MethylationArray identified differentially methylated CpG sites between ASD and controls that mapped to 898 genes (P ??0.05) which were enriched for nine canonical pathways converging on mitochondrial metabolism and protein ubiquitination. Targeted Next Generation Bisulfite Sequencing of 27 genes confirmed differential methylation between ASD and control in our cohort. DNA pyrosequencing of two of these genes, the mitochondrial enzyme Propionyl-CoA Carboxylase subunit Beta (PCCB) and Protocadherin Alpha 12 (PCDHA12), revealed a wide range of methylation levels (9-49% and 0-54%, respectively) in both ASD and controls. Three CpG loci were differentially methylated in PCCB (P ??0.05), while PCDHA12, previously linked to ASD, had two significantly different CpG sites (P ??0.001) between ASD and control. Differentially methylated CpGs were hypomethylated in ASD. Metabolomic analysis of urinary organic acids revealed that three metabolites, 3-hydroxy-3-methylglutaric acid (P =?0.008), 3-methyglutaconic acid (P =?0.018), and ethylmalonic acid (P =?0.043) were significantly elevated in individuals with ASD. These metabolites are directly linked to mitochondrial respiratory chain disorders, with a putative link to PCCB, consistent with impaired mitochondrial function. Our data support an association between DNA methylation and mitochondrial dysfunction in the etiology of ASD. Autism Res 2020, 13: 1079-1093. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Epigenetic changes are chemical modifications of DNA which can change gene function. DNA methylation, a type of epigenetic modification, is linked to autism. We examined DNA methylation in South African children with autism and identified mitochondrial genes associated with autism. Mitochondria are power-suppliers in cells and mitochondrial genes are essential to metabolism and energy production, which are important for brain cells during development. Our findings suggest that some individuals with ASD also have mitochondrial dysfunction. En ligne : http://dx.doi.org/10.1002/aur.2310 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=429 [article] DNA Methylation Associated with Mitochondrial Dysfunction in a South African Autism Spectrum Disorder Cohort [Texte imprimé et/ou numérique] / Sofia STATHOPOULOS, Auteur ; Renaud GAUJOUX, Auteur ; Zander LINDEQUE, Auteur ; Caitlyn MAHONY, Auteur ; Rachelle VAN DER COLFF, Auteur ; Francois VAN DER WESTHUIZEN, Auteur ; Colleen O'RYAN, Auteur . - p.1079-1093. Langues : Anglais (eng) in Autism Research > 13-7 (July 2020) . - p.1079-1093 Mots-clés : Autism Spectrum Disorder  DNA methylation  Pccb  Pcdha12  epigenetics  metabolomic profiles  mitochondrial dysfunction  organic acids Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is characterized by phenotypic heterogeneity and a complex genetic architecture which includes distinctive epigenetic patterns. We report differential DNA methylation patterns associated with ASD in South African children. An exploratory whole-epigenome methylation screen using the Illumina 450?K MethylationArray identified differentially methylated CpG sites between ASD and controls that mapped to 898 genes (P ??0.05) which were enriched for nine canonical pathways converging on mitochondrial metabolism and protein ubiquitination. Targeted Next Generation Bisulfite Sequencing of 27 genes confirmed differential methylation between ASD and control in our cohort. DNA pyrosequencing of two of these genes, the mitochondrial enzyme Propionyl-CoA Carboxylase subunit Beta (PCCB) and Protocadherin Alpha 12 (PCDHA12), revealed a wide range of methylation levels (9-49% and 0-54%, respectively) in both ASD and controls. Three CpG loci were differentially methylated in PCCB (P ??0.05), while PCDHA12, previously linked to ASD, had two significantly different CpG sites (P ??0.001) between ASD and control. Differentially methylated CpGs were hypomethylated in ASD. Metabolomic analysis of urinary organic acids revealed that three metabolites, 3-hydroxy-3-methylglutaric acid (P =?0.008), 3-methyglutaconic acid (P =?0.018), and ethylmalonic acid (P =?0.043) were significantly elevated in individuals with ASD. These metabolites are directly linked to mitochondrial respiratory chain disorders, with a putative link to PCCB, consistent with impaired mitochondrial function. Our data support an association between DNA methylation and mitochondrial dysfunction in the etiology of ASD. Autism Res 2020, 13: 1079-1093. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Epigenetic changes are chemical modifications of DNA which can change gene function. DNA methylation, a type of epigenetic modification, is linked to autism. We examined DNA methylation in South African children with autism and identified mitochondrial genes associated with autism. Mitochondria are power-suppliers in cells and mitochondrial genes are essential to metabolism and energy production, which are important for brain cells during development. Our findings suggest that some individuals with ASD also have mitochondrial dysfunction. En ligne : http://dx.doi.org/10.1002/aur.2310 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=429

Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism / Michael S. BREEN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 53 p. Titre : Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism Type de document : Texte imprimé et/ou numérique Auteurs : Michael S. BREEN, Auteur ; Andrew BROWNE, Auteur ; Gabriel E. HOFFMAN, Auteur ; Sofia STATHOPOULOS, Auteur ; Kristen BRENNAND, Auteur ; Joseph D. BUXBAUM, Auteur ; Elodie DRAPEAU, Auteur Article en page(s) : 53 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Neural progenitor cells  Neurons  RNA-sequencing  Stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder with high risk of autism spectrum disorder (ASD), intellectual disability, and language delay, and is caused by 22q13.3 deletions or mutations in the SHANK3 gene. To date, the molecular and pathway changes resulting from SHANK3 haploinsufficiency in PMS remain poorly understood. Uncovering these mechanisms is critical for understanding pathobiology of PMS and, ultimately, for the development of new therapeutic interventions. METHODS: We developed human-induced pluripotent stem cell (hiPSC)-based models of PMS by reprogramming peripheral blood samples from individuals with PMS (n = 7) and their unaffected siblings (n = 6). For each participant, up to three hiPSC clones were generated and differentiated into induced neural progenitor cells (hiPSC-NPCs; n = 39) and induced forebrain neurons (hiPSC-neurons; n = 41). Genome-wide RNA-sequencing was applied to explore transcriptional differences between PMS probands and unaffected siblings. RESULTS: Transcriptome analyses identified 391 differentially expressed genes (DEGs) in hiPSC-NPCs and 82 DEGs in hiPSC-neurons, when comparing cells from PMS probands and unaffected siblings (FDR En ligne : http://dx.doi.org/10.1186/s13229-020-00355-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism [Texte imprimé et/ou numérique] / Michael S. BREEN, Auteur ; Andrew BROWNE, Auteur ; Gabriel E. HOFFMAN, Auteur ; Sofia STATHOPOULOS, Auteur ; Kristen BRENNAND, Auteur ; Joseph D. BUXBAUM, Auteur ; Elodie DRAPEAU, Auteur . - 53 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 53 p. Mots-clés : Autism spectrum disorder  Neural progenitor cells  Neurons  RNA-sequencing  Stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder with high risk of autism spectrum disorder (ASD), intellectual disability, and language delay, and is caused by 22q13.3 deletions or mutations in the SHANK3 gene. To date, the molecular and pathway changes resulting from SHANK3 haploinsufficiency in PMS remain poorly understood. Uncovering these mechanisms is critical for understanding pathobiology of PMS and, ultimately, for the development of new therapeutic interventions. METHODS: We developed human-induced pluripotent stem cell (hiPSC)-based models of PMS by reprogramming peripheral blood samples from individuals with PMS (n = 7) and their unaffected siblings (n = 6). For each participant, up to three hiPSC clones were generated and differentiated into induced neural progenitor cells (hiPSC-NPCs; n = 39) and induced forebrain neurons (hiPSC-neurons; n = 41). Genome-wide RNA-sequencing was applied to explore transcriptional differences between PMS probands and unaffected siblings. RESULTS: Transcriptome analyses identified 391 differentially expressed genes (DEGs) in hiPSC-NPCs and 82 DEGs in hiPSC-neurons, when comparing cells from PMS probands and unaffected siblings (FDR En ligne : http://dx.doi.org/10.1186/s13229-020-00355-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

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