Target Genes of Autism Risk Loci in Brain Frontal Cortex

Sun, Yan; Yao, Xueming; March, Michael; Meng, Xinyi; Li, Junyi; Wei, Zhi; Sleiman, Patrick; Hákonarson, Hákon; Xia, Qianghua; Li, Jin

doi:10.3389/fgene.2019.00707

Cited by 17 publications

(13 citation statements)

References 61 publications

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“…Interestingly, ABCF1 has been suggested to be one of the putative therapeutic targets for escitalopram, an SSRI treatment used for both depressive symptoms and anxiety [ 36 ]. Altered methylation of ABCF1 has also been seen to be associated with autism in an in silico analysis multi-omics data analysis including frontal cortex samples [ 37 ]. Previous studies investigating the association between PND with anxiety symptoms and cord blood DNA methylation have not compared with PND alone compared with healthy controls [ 16 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

DNA methylation in cord blood in association with prenatal depressive symptoms

et al. 2021

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Background Prenatal symptoms of depression (PND) and anxiety affect up to every third pregnancy. Children of mothers with mental health problems are at higher risk of developmental problems, possibly through epigenetic mechanisms together with other factors such as genetic and environmental. We investigated DNA methylation in cord blood in relation to PND, taking into consideration a history of depression, co-morbidity with anxiety and selective serotonin reuptake inhibitors (SSRI) use, and stratified by sex of the child. Mothers (N = 373) prospectively filled out web-based questionnaires regarding mood symptoms and SSRI use throughout pregnancy. Cord blood was collected at birth and DNA methylation was measured using Illumina MethylationEPIC array at 850 000 CpG sites throughout the genome. Differentially methylated regions were identified using Kruskal–Wallis test, and Benjamini-Hochberg adjusted p-values < 0.05 were considered significant. Results No differential DNA methylation was associated with PND alone; however, differential DNA methylation was observed in children exposed to comorbid PND with anxiety symptoms compared with healthy controls in ABCF1 (log twofold change − 0.2), but not after stratification by sex of the child. DNA methylation in children exposed to PND without SSRI treatment and healthy controls both differed in comparison with SSRI exposed children at several sites and regions, among which hypomethylation was observed in CpGs in the promoter region of CRBN (log2 fold change − 0.57), involved in brain development, and hypermethylation in MDFIC (log2 fold change 0.45), associated with the glucocorticoid stress response. Conclusion Although it is not possible to assess if these methylation differences are due to SSRI treatment itself or to more severe depression, our findings add on to existing knowledge that there might be different biological consequences for the child depending on whether maternal PND was treated with SSRIs or not.

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Section: Discussionmentioning

confidence: 99%

DNA methylation in cord blood in association with prenatal depressive symptoms

et al. 2021

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“…In our studies, we did not examine the effect of a metal deficiency ( Grabrucker et al, 2017 ) or excess ( Amal et al, 2020b ) on the development of an autistic phenotype, but we did examine how the administration of toxins (VPA or THAL) that induced autism-like behavior influenced the distribution of metals in the rat brain. The subject of the study of this work were three regions of the brain: CC, HPC, and CE, because their developmental disorders are particularly strongly associated with ASD pathogenesis ( Varghese et al, 2017 ; Bruchhage et al, 2018 ; Sun et al, 2019 ). In previous studies, also done on the THAL- and/or VPA-induced rat models of autism we showed changes in the content of neuroactive amino acids in the hippocampus ( Zieminska et al, 2018 ), and then we did the metabolomic profiles of this area of the brain ( Toczylowska et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Zinc and Copper Brain Levels and Expression of Neurotransmitter Receptors in Two Rat ASD Models

Ziemińska

Ruszczyńska

Augustyniak

et al. 2021

Front. Mol. Neurosci.

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Zinc and copper are important trace elements necessary for the proper functioning of neurons. Impaired zinc and/or copper metabolism and signaling are implicated in many brain diseases, including autism (ASD). In our studies, autistic-like behavior in rat offsprings was induced by application to pregnant mothers valproic acid or thalidomide. Zinc and copper contents were measured in serum and brain structures: hippocampus, cerebral cortex, and cerebellum. Our research shows no interconnections in the particular metal concentrations measured in autistic animal brains and their sera. Based on patient researches, we studied 26 genes belonging to disturbed neurotransmitter pathways. In the same brain regions, we examined the expression of genes encoding proteins of cholinergic, adrenergic, serotonin, and dopamine receptors. In both rats’ ASD models, 17 out of the tested gene expression were decreased. In the cerebellum and cerebral cortex, expression of genes encoding cholinergic, adrenergic, and dopaminergic receptors decreased, whereas in the hippocampus only expression of serotoninergic receptors genes was downregulated. The changes in metals content observed in the rat brain can be secondary phenomena, perhaps elements of mechanisms that compensate for neurotransmission dysfunctions.

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“…Moreover, recent studies have described a reduction of essential amino acid levels and sex-specific alterations in serum amino acid concentration profiles in children with autism spectrum disorder, and an increasing number of studies indicate that patients with ASD may have unique metabolic patterns with a variety of amino acid metabolism dysregulations [28,29]. Based on these observations, the analysis of chromosomes, focusing particularly on chromosome 15, could exploit the chromosome walking approach to discover differences in the amino acid composition of proteins codified by the reported ASD loci [30][31][32] and could reveal further critical regions. Although there are many influencing factors, the base composition is considered as the driving force in amino acid usage.…”

Section: Discussionmentioning

confidence: 99%

Chromosome Walking: A Novel Approach to Analyse Amino Acid Content of Human Proteins Ordered by Gene Position

et al. 2021

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Notwithstanding the huge amount of detailed information available in protein databases, it is not possible to automatically download a list of proteins ordered by the position of their codifying gene. This order becomes crucial when analyzing common features of proteins produced by loci or other specific regions of human chromosomes. In this study, we developed a new procedure that interrogates two human databases (genomic and protein) and produces a novel dataset of ordered proteins following the mapping of the corresponding genes. We validated and implemented the procedure to create a user-friendly web application. This novel data mining was used to evaluate the distribution of critical amino acid content in proteins codified by a human chromosome. For this purpose, we designed a new methodological approach called chromosome walking, which scanned the whole chromosome and found the regions producing proteins enriched in a selected amino acid. As an example of biomedical application, we investigated the human chromosome 15, which contains the locus DYX1 linked to developmental dyslexia, and we found three additional putative gene clusters whose expression could be driven by the environmental availability of glutamate. The novel data mining procedure and analysis could be exploited in the study of several human pathologies.

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Target Genes of Autism Risk Loci in Brain Frontal Cortex

Cited by 17 publications

References 61 publications

DNA methylation in cord blood in association with prenatal depressive symptoms

DNA methylation in cord blood in association with prenatal depressive symptoms

Zinc and Copper Brain Levels and Expression of Neurotransmitter Receptors in Two Rat ASD Models

Chromosome Walking: A Novel Approach to Analyse Amino Acid Content of Human Proteins Ordered by Gene Position

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