Using a nested case-cohort design within an Australian population-derived prebirth cohort study, placental transcriptomic signature of impaired mitochondrial function and gene transcription regulation among infants subsequently diagnosed with autism has profound implications for understanding both risk factors and prediction.
Abstract
Autism development involves multiple genetic and early-life environmental factors. Studying the placenta's gene expression profile may reveal key mechanistic pathways in autism development. Here, using a nested case-cohort design within an Australian population-derived prebirth cohort study (n=1074), we identified 1,644 differentially expressed genes (DEGs; FDR<0.05) in the placenta of children with autism diagnosis (n=43), compared to those without (n=120). The top enriched pathways related to mitochondrial translation, oxidative stress, RNA processing and transcription regulation. CYP1A1, the most important xenobiotic-metabolising enzyme of the placenta, was the top downregulated DEG in the placenta of children with autism, while immuno-regulatory human leukocyte antigen (HLA)-related genes were among the top upregulated DEGs. A machine learning-based approach predicted autism from the transcriptomic data with a median sensitivity of 0.57 (2.5th-97.5th centiles: 0.29, 0.76) and median specificity of 0.92 (2.5th-97.5th centiles: 0.78, 0.98). Weighted Gene Correlation Network Analysis identified eight affected placental gene modules, with the largest five modules being enriched primarily for mitochondrial bioenergetics, oxidative phosphorylation and RNA processing pathways. This placental transcriptomic signature of impaired mitochondrial function and gene transcription regulation among infants subsequently diagnosed with autism has profound implications for understanding both risk factors and prediction, suggesting the possibility of identifying modifiable prenatal pathways to improve autism outcomes.
This study integrated mRNA expression profiles from five post-mortem brain tissue GEO datasets to identify ASD-associated genes and found that EIF4A1 mRNA expression was significantly elevated in ASD subjects and rescued by treatment with the antipsychotics olanzapine or risperidone.
Findings indicate that CASP4 and TLR8, together with their associated regulatory miRNAs, may represent promising biomarkers and potential therapeutic targets for future ASD research and contribute to a better understanding of the pathophysiological mechanisms underlying ASD.
Sara Hosseinpoor, H. Zali, Hassan Zohrevand et al.· PLoS ONE· 0 citations
RNA-sequencing, 3-dimensional protein-centric chromatin conformation, and whole genome DNA methylation sequencing approaches are used to investigate hippocampal tissue from an ASD mouse model to determine if multi-omic data integration improves the resolution of key molecular pathways contributing to the complex ASD phenotype.
Carolina D Alberca, Kwangmoon Park, Ligia A. Papale et al.· Molecular Psychiatry· 0 citations
Background The placenta has a unique transcriptomic profile, including microRNAs that are secreted into maternal circulation throughout pregnancy. MicroRNAs are small, non-coding RNA that post-transcriptionally regulate gene expression. Spontaneous preterm birth (sPTB) is associated with substantial differences in both placental pathophysiology and placental gene expression compared to term birth. We aimed to generate microRNA signatures of sPTB and map them to target genes using a microRNA–mRNA network. Methods This study was conducted within the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study. Placental samples were collected at delivery, and RNA was isolated for mRNA and microRNA sequencing. To investigate sPTB, this study excluded placental samples of participants with iatrogenic indications for PTB or induced labor. We examined differences in microRNA expression in participants who delivered before 37 weeks (N=35) compared to term participants (N=404) in a series of covariate-adjusted linear regression models. We used paired placental microRNA and mRNA expression data from this cohort to validate associations between computationally predicted microRNA–mRNA pairs and establish a microRNA–mRNA network. Results Expression of 7 microRNAs were increased in sPTB (FDR<0.05) and were inversely correlated with sPTB-associated genes involved in immune signaling. Expression of 12 microRNAs were decreased in sPTB, including 4 members of the maternally expressed chromosome 14 microRNA cluster (miR-376a-3p, miR-376c-3p, miR-377-3p, and miR-381-3p). These microRNAs were predicted to negatively regulate oxidative phosphorylation genes that were increased in sPTB. The associations between miR-376c-3p and miR-377-3p and oxidative phosphorylation were confirmed in microRNA knockdown experiments. Conclusions This study highlights potential biological mechanisms by which placental microRNA dysfunction might contribute to sPTB and highlights putative sPTB biomarkers that may be detectable in maternal circulation.
Mariana Parenti, Elizabeth M. Kennedy, Evan J. Firsick et al.· bioRxiv· 0 citations
A high-resolution placental mQTL resource is constructed and systematically investigated how placental DNAm relates to early- and later-life traits, and to shared vulnerability and complex interactions among them.
A. Cilleros-Portet, Itziar González-Moro, Hachem Sadikki et al.· medRxiv· 0 citations
Postpartum depression (PPD) is among the most common complications of childbirth, and identifying novel treatments is vital. We aimed to identify potential drug targets for PPD by integrating the plasma proteome, transcriptome and epigenome. We designed a comprehensive analysis pipeline involving two-sample Mendelian randomisation (MR) (for proteins), colocalisation (for coding genes), and summary-based MR (SMR) (for mRNA and DNA methylation) to identify potential therapeutic targets for PPD. Genetic data on the plasma proteome were obtained from 4907 aptamers in 35,559 Icelanders and 7596 proteins in 828 FinnGen participants. The PPD genome-wide association study data were sourced from the Psychiatric Genomics Consortium (PGC) (Ncase = 17,339, Ncontrol = 53,426). A two-step MR approach was used to assess whether brain imaging-derived phenotypes (IDPs) and metabolites from blood, brain and cerebrospinal fluid mediated the observed effects. Across the two proteome datasets, the genetically predicted levels of 18 plasma proteins were nominally significantly associated with PPD, and the expression of steroid receptor RNA activator 1 (SRA1), a regulator of steroid hormone signalling, was significantly associated with PPD. SRA1, angiotensinogen (AGT, a key mediator of the renin-angiotensin and stress-response system), and glycerol-3-phosphate phosphatase (PGP, involved in lipid metabolism and cellular stress) showed increased colocalisation. The methylation of SRA1 at cg02434007 in the brain was associated with increased expression of SRA1 and a high risk of PPD, which aligns with the positive effect of SRA1 gene expression on PPD risk. Isoleucine (mediation proportion: 5.8%, p = 0.042) from blood metabolites and the IDP ICA100 edge 442 (mediation proportion: 7.6%, p = 0.044) may play mediating roles. This study reveals that SRA1 is a novel therapeutic target for PPD, which enhances the understanding of its molecular aetiology and the development of therapeutic strategies.
Ming Chen, Qinlin Wei, Hao-Wen Li et al.· npj Mental Health Research· 0 citations
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