Non-coding RNAs in depression: Promising diagnostic and therapeutic biomarkers

Shi, Yachen; Wang, Qingyun; Song, Ruize; Kong, Yan; Zhang, Zhijun

doi:10.1016/j.ebiom.2021.103569

Cited by 45 publications

(44 citation statements)

References 123 publications

(126 reference statements)

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“…For example, miRNA mimics or inhibitors could be used to manipulate transcript expression alongside or in place of RNA interference (RNAi) methods. These new approaches could be useful for laboratory-based functional genomics, or even as new avenues for control [miRNAs have been suggested as therapeutic targets in various human diseases ( Marracino et al., 2021 ; Shi et al., 2021 ; Smit-McBride and Morse, 2021 )]. Furthermore, inhibiting EV release from helminths would conceivably prevent delivery of miRNAs (and other bioactive molecules) to host immune cells.…”

Section: Discussionmentioning

confidence: 99%

Developmental Regulation and Functional Prediction of microRNAs in an Expanded Fasciola hepatica miRNome

Herron

O’Connor

Robb

et al. 2022

Front. Cell. Infect. Microbiol.

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The liver fluke, Fasciola hepatica, is a global burden on the wellbeing and productivity of farmed ruminants, and a zoonotic threat to human health. Despite the clear need for accelerated discovery of new drug and vaccine treatments for this pathogen, we still have a relatively limited understanding of liver fluke biology and host interactions. Noncoding RNAs, including micro (mi)RNAs, are key to transcriptional regulation in all eukaryotes, such that an understanding of miRNA biology can shed light on organismal function at a systems level. Four previous publications have reported up to 89 mature miRNA sequences from F. hepatica, but our data show that this does not represent a full account of this species miRNome. We have expanded on previous studies by sequencing, for the first time, miRNAs from multiple life stages (adult, newly excysted juvenile (NEJ), metacercariae and adult-derived extracellular vesicles (EVs)). These experiments detected an additional 61 high-confidence miRNAs, most of which have not been described in any other species, expanding the F. hepatica miRNome to 150 mature sequences. We used quantitative (q)PCR assays to provide the first developmental profile of miRNA expression across metacercariae, NEJ, adult and adult-derived Evs. The majority of miRNAs were expressed most highly in metacercariae, with at least six distinct expression clusters apparent across life stages. Intracellular miRNAs were functionally analyzed to identify target mRNAs with inversely correlated expression in F. hepatica tissue transcriptomes, highlighting regulatory interactions with key virulence transcripts including cathepsin proteases, and neuromuscular genes that control parasite growth, development and motility. We also linked 28 adult-derived EV miRNAs with downregulation of 397 host genes in F. hepatica-infected transcriptomes from ruminant lymph node, peripheral blood mononuclear cell (PBMC) and liver tissue transcriptomes. These included genes involved in signal transduction, immune and metabolic pathways, adding to the evidence for miRNA-based immunosuppression during fasciolosis. These data expand our understanding of the F. hepatica miRNome, provide the first data on developmental miRNA regulation in this species, and provide a set of testable hypotheses for functional genomics interrogations of liver fluke miRNA biology.

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Section: Discussionmentioning

confidence: 99%

Developmental Regulation and Functional Prediction of microRNAs in an Expanded Fasciola hepatica miRNome

Herron

O’Connor

Robb

et al. 2022

Front. Cell. Infect. Microbiol.

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“…ZNRD2-DT is a lncRNA and interestingly our ndings include several IncRNAs in the set of pGenes as well as related with regulatory variations, either colocalizing with cis-eQTLS (RP11-894P9.2 and RP5-1115A15.1) or with mechanistic evidence for its association with gene expression regulation (ZNRD2-DT). Although not being clear their exact role in MD pathophysiology, ncRNAs have been described as promising biomarkers and drug targets for MD [59,60].…”

Section: Discussionmentioning

confidence: 99%

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Pérez-Granado

Piñero

Medina-Rivera

et al. 2022

Preprint

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Background: Major Depression is the leading cause of impairment worldwide. The understanding of its molecular underpinnings is key to identifying new potential biomarkers and drug targets to alleviate its burden in society. Leveraging available GWAS data and functional genomic tools to assess regulatory variation could help explain the role of Major Depression associated genetic variants in disease pathogenesis. We have conducted a fine-mapping analysis of genetic variants associated with Major Depression and applied a pipeline focused on gene expression regulation by using two complementary approaches: cis-eQTL colocalization analysis using GTEx data and alteration of transcription factor binding sites with pattern matching approaches and chromatin accessibility data.Results: The fine-mapping of major depression genetic variants uncovered putative causally associated variants whose proximal genes were linked with Major Depression pathophysiology. Four genetic variants altering the expression of 5 genes were found by colocalization analysis, highlighting the role of SLC12A5, involved in chlorine homeostasis in neurons, and MYRF, related with central nervous system myelination and oligodendrocyte differentiation. The transcription factor binding analysis revealed the potential role of the genomic variant rs62259947 in modulating the expression of P4HTM through the alteration of YY1 binding site, altogether regulating hypoxia response.Conclusions: The combination of GWAS signals, cis-eQTL, transcription factor binding site information and active regulatory regions in the chromatin, enabled the prioritization of putative causal genetic variants in Major Depression. Importantly, our pipeline can be applied when only index genetic variants are available. Finally, the presented approach enabled the proposal of mechanistic hypotheses of these genetic variants and their role in disease pathogenesis.

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“…NRD2-DT is a lncRNA, and interestingly, our findings include several IncRNAs in the set of pGenes as well as related with regulatory variations, either colocalizing with cis-eQTLS (RP11-894P9.2 and RP5-1115A15.1) or with mechanistic evidence for its association with gene expression regulation (ZNRD2-DT). Although not their exact role in MD pathophysiology is not clear, ncRNAs have been described as promising biomarkers and drug targets for MD [ 75 , 76 ].…”

Section: Discussionmentioning

confidence: 99%

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Pérez-Granado

Piñero

Medina-Rivera

et al. 2022

Genes

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Understanding the molecular basis of major depression is critical for identifying new potential biomarkers and drug targets to alleviate its burden on society. Leveraging available GWAS data and functional genomic tools to assess regulatory variation could help explain the role of major depression-associated genetic variants in disease pathogenesis. We have conducted a fine-mapping analysis of genetic variants associated with major depression and applied a pipeline focused on gene expression regulation by using two complementary approaches: cis-eQTL colocalization analysis and alteration of transcription factor binding sites. The fine-mapping process uncovered putative causally associated variants whose proximal genes were linked with major depression pathophysiology. Four colocalizing genetic variants altered the expression of five genes, highlighting the role of SLC12A5 in neuronal chlorine homeostasis and MYRF in nervous system myelination and oligodendrocyte differentiation. The transcription factor binding analysis revealed the potential role of rs62259947 in modulating P4HTM expression by altering the YY1 binding site, altogether regulating hypoxia response. Overall, our pipeline could prioritize putative causal genetic variants in major depression. More importantly, it can be applied when only index genetic variants are available. Finally, the presented approach enabled the proposal of mechanistic hypotheses of these genetic variants and their role in disease pathogenesis.

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Non-coding RNAs in depression: Promising diagnostic and therapeutic biomarkers

Cited by 45 publications

References 123 publications

Developmental Regulation and Functional Prediction of microRNAs in an Expanded Fasciola hepatica miRNome

Developmental Regulation and Functional Prediction of microRNAs in an Expanded Fasciola hepatica miRNome

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

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