Emerging Roles of FTO in Neuropsychiatric Disorders

Chang, Rui; Huang, Zeyi; Zhao, Size; Zou, Jiong; Li, Yukun; Tan, Sisi

doi:10.1155/2022/2677312

Cited by 16 publications

(7 citation statements)

References 112 publications

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“…The two most significant loci exerted opposite directions of effect for BMI and AUD. The first was an intronic variant (rs9939973) in the well-known obesity risk gene, FTO (also linked to numerous other traits, including substance use disorders, major depression, and schizophrenia; Chang et al, 2022). The second was an intronic variant (rs13114738) in the highly pleiotropic gene SLC39A8 (Pickrell et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations

Malone,

Davis,

Piserchia

et al. 2024

Preprint

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Background: The prevalence of co-occurring heavy alcohol consumption and obesity is increasing in the United States. Despite neurobiological overlap in the regulation of alcohol consumption and eating behavior, alcohol- and body mass index (BMI)-related phenotypes show no or minimal genetic correlation. We hypothesized that the lack of genetic correlation is due to mixed effect directions of variants shared by AUD and BMI. Methods: We applied MiXeR, to investigate shared genetic architecture between AUD and BMI in individuals of European ancestry. We used conjunctional false discovery rate (conjFDR) analysis to detect loci associated with both phenotypes and their directional effect, Functional Mapping and Annotation (FUMA) to identify lead single nucleotide polymorphisms (SNPs), Genotype-Tissue Expression (GTEx) samples to examine gene expression enrichment across tissue types, and BrainXcan to evaluate the shared associations of AUD and BMI with brain image-derived phenotypes. Results: MiXeR analysis indicated polygenic overlap of 80.9% between AUD and BMI, despite a genetic correlation (rg) of -.03. ConjFDR analysis yielded 56 lead SNPs with the same effect direction and 76 with the opposite direction. Of the 132 shared lead SNPs, 53 were novel for both AUD and BMI. GTEx analyses identified significant overexpression in the frontal cortex (BA9), hypothalamus, cortex, anterior cingulate cortex (BA24), hippocampus, and amygdala. Amygdala and caudate nucleus gray matter volumes were significantly associated with both AUD and BMI in BrainXcan analyses. Conclusions: More than half of variants significantly associated with AUD and BMI had opposite directions of effect for the traits, supporting our hypothesis that this is the basis for their lack of genetic correlation. Follow-up analyses identified brain regions implicated in executive functioning, reward, homeostasis, and food intake regulation. Together, these findings clarify the extensive polygenic overlap between AUD and BMI and elucidate several overlapping neurobiological mechanisms.

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Section: Resultsmentioning

confidence: 99%

Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations

Malone,

Davis,

Piserchia

et al. 2024

Preprint

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“…M6A is first converted to hm6A, then transformed to fm6A, and finally reduced to original adenylate ( 34 , 35 ). FTO is enriched in brain, especially in neurons, and plays an important regulatory role in central nervous system (CNS), including brain development and function ( 36 ). Dysregulation of FTO may participate in CNS injuries such as TBI.…”

Section: Discussionmentioning

confidence: 99%

Expression characteristics of circular RNA in human traumatic brain injury

et al. 2023

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Traumatic brain injury (TBI) causes high rates of worldwide mortality and morbidity due to the complex secondary injury cascade. Recently, circular ribonucleic acids (circRNAs) have attracted significant attention in a variety of diseases. However, their expression characteristics in human TBI are still unclear. In this study, we examined brain injury tissues from six severe TBI patients in Jinling Hospital. The TBI tissues and adjacent brain contusion tissues were used to analyze differential expression signatures of circRNAs through full-length transcriptome sequencing, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and ceRNA network construction. Our results found that there were 126 differently expressed circRNAs in TBI. Among them, 64 circRNAs were up-regulated and 62 circRNAs were down-regulated. Moreover, GO and KEGG analyses revealed that the aberrantly expressed circRNAs participated in many pathophysiological processes of TBI, especially regarding microglial cell activation, protein transport, protein processing and inflammation. Furthermore, the ceRNA (circRNA-miRNA-mRNA) network predicted that there existed strong relationship among circRNA, miRNA and mRNA. Taken together, our results indicated for the first time that the expression profiles of circRNAs were different after human TBI. In addition, we found the signaling pathways that were related to circRNAs and predicted a ceRNA network, which provided new insight of circRNAs in human TBI.

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“…With the recent advent of epitranscriptomic modification, such dynamism in gene regulation may occur in concert with m 6 A RNA methylation, the most prevalent type of epitranscriptomic modification in the brain ( Chang et al, 2017 ). In this context, it is important to note that FTO plays a significant role not only in the processing of m 6 A enrichment on a gene, but it has a direct role in brain development and function ( Widagdo and Anggono, 2018 ; Chang et al, 2022 ). The FTO gene is abundantly expressed in the brain and participates in neurogenesis ( Li et al, 2017b ; Gao et al, 2020 ; Du et al, 2021 ) and memory deficits ( Walters et al, 2017 ; Spychala and Ruther, 2019 ; Leonetti et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

M6A RNA Methylation-Based Epitranscriptomic Modifications in Plasticity-Related Genes via miR-124-C/EBPα-FTO-Transcriptional Axis in the Hippocampus of Learned Helplessness Rats

Roy

Ochi

Dwivedi

2022

International Journal of Neuropsychopharmacology

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Background Impaired synaptic plasticity has been linked to dynamic gene regulatory network changes. Recently, gene regulation has been introduced with the emerging concept of unique m 6A-based reversible transcript methylation. In this study, we tested whether m 6A RNA methylation may potentially serve as a link between the stressful insults and altered expression of plasticity-related genes. Methods Expression of plasticity genes Nr3c1, Creb1, Ntrk2; m6A modifying enzymes Fto, Mettl3, Mettl14; DNA methylation enzymes Dnmt1, Dnmt3a; transcription factor C/ebp-α; and miRNA-124-3p were determined by qPCR in the hippocampus of rats who showed susceptibility to develop stress-induced depression (learned helplessness, LH). M 6A methylation of plasticity-related genes was determined following m 6A mRNA immunoprecipitation. Chromatin immunoprecipitation was used to examine the endogenous binding of C/EBP-αto the Fto promoter. MiR-124-mediated post-transcriptional inhibition of Fto via C/EBPα was determined using an in-vitro model. Results Hippocampus of LH rats showed downregulation of Nr3c1, Creb1, and Ntrk2 along with enrichment in their m 6A methylation. A downregulation in demethylating enzyme Fto and upregulation in methylating enzyme Mettl3 were also noted. The Fto promoter was hypomethylated due to the lower expression of Dnmt1 and Dnmt3a. At the same time, there was a lower occupancy of transcription factor C/EBPα on the Fto promoter. Conversely, C/ebp-α transcript was downregulated via induced miR-124-3p expression. Conclusions Our study mechanistically linked defective C/EBP-α-FTO-axis, epigenetically influenced by induced expression of miR-124-3p, in modifying m 6A enrichment in plasticity-related genes. This could potentially be linked with abnormal neuronal plasticity in depression.

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Emerging Roles of FTO in Neuropsychiatric Disorders

Cited by 16 publications

References 112 publications

Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations

Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations

Expression characteristics of circular RNA in human traumatic brain injury

M6A RNA Methylation-Based Epitranscriptomic Modifications in Plasticity-Related Genes via miR-124-C/EBPα-FTO-Transcriptional Axis in the Hippocampus of Learned Helplessness Rats

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