scholarly journals Genome-wide translating mRNA analysis following ketamine reveals novel targets for antidepressant treatment

2018 ◽  
Author(s):  
Oliver H. Miller ◽  
Nils Grabole ◽  
Isabelle Wells ◽  
Benjamin J. Hall
Keyword(s):  
Protein Synthesis ◽  
Low Dose ◽  
Antidepressant Treatment ◽  
Enrichment Analysis ◽  
Protein Product ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Antidepressant Effects ◽  
Novel Target

AbstractLow-dose ketamine is an efficacious antidepressant for treatment-resistant unipolar and bipolar depressed patients. Major Depression Disorder patients receiving a single infusion report elevated mood within two hours, and ketamine’s antidepressant effects have been observed as long as seven days post-treatment. In light of this remarkable observation, efforts have been undertaken to “reverse-translate” ketamine’s effects to understand its mechanism of action. Major advances have been achieved in understanding the molecular, cellular, and circuit level changes that are initiated by low-dose ketamine. Although enhancement of protein synthesis clearly plays a role, the field lacks a comprehensive understanding of the protein synthesis program initiated after ketamine treatment. Here, using ribosome-bound mRNA footprinting and deep sequencing (RiboSeq), we uncover a genome-wide set of actively translated mRNAs (the translatome) in medial prefrontal cortex after an acute antidepressant-like dose of ketamine. Gene Ontology analysis confirmed that initiation of protein synthesis is a defining feature of antidepressant-dose ketamine in mice and Gene Set Enrichment Analysis points to a role for GPCR signaling, metabolism, vascularization, and structural plasticity in ketamine’s effects. One gene, VIPR2, whose protein product VPAC2 acts as a GPCR for the neuropeptide vasoactive intestinal peptide, was characterized in cortex and identified as a potential novel target for antidepressant action.

scholarly journals Genome-Wide Association Study of Postoperative Cognitive Dysfunction in Older Surgical Patients

2020 ◽  
Author(s):  
Marc Rickenbacher ◽  
Céline S Reinbold ◽  
Stefan Herms ◽  
Per Hoffmann ◽  
Sven Cichon ◽  
...  
Keyword(s):  
Association Study ◽  
Candidate Genes ◽  
Cognitive Dysfunction ◽  
Genome Wide Association Study ◽  
Postoperative Cognitive Dysfunction ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

Abstract Background: Postoperative cognitive dysfunction (POCD) is a common neurocognitive complication after surgery and anesthesia, particularly in elderly patients. Various studies have suggested genetic risk factors for POCD. The study aimed to detect genome-wide associations of POCD in older patients.Methods: In this prospective observational cohort study, participants aged ≥65 years completed a set of neuropsychological tests before, at 1 week, and 3 months after major noncardiac surgery. Test variables were converted into standard scores (z-scores) based on demographic characteristics. POCD was diagnosed if the decline was >1 standard deviation in ≥2 of the 15 variables in the assessment battery. A genome-wide association study (GWAS) was performed to determine potential alleles that are linked to the POCD phenotype. In addition, candidate genes for POCD were identified in a literature search for further analysis.Results: Sixty-three patients with blood samples were included in the study. POCD was diagnosed in 47.6% of patients at 1 week and in 34.2% of patients at 3 months after surgery. Insufficient sample quality led to exclusion of 26 patients. In the remaining 37 patients, a GWAS was performed, but no association (P < 5*10-8) with POCD was found. The subsequent gene set enrichment analysis of 34 candidate genes did not reveal any significant associations.Conclusion: In this patient cohort, a GWAS did not reveal an association between specific genetic alleles and POCD at 1 week and 3 months after surgery. Future genetic analysis should focus on specific candidate genes for POCD.Trial registration: ClinicalTrials.gov (NCT02864173)

scholarly journals In vivo CRISPR/Cas9 knockout screen: TCEAL1 silencing enhances docetaxel efficacy in prostate cancer

2020 ◽  
Vol 3 (12) ◽  
pp. e202000770 ◽  
Author(s):  
Linda K Rushworth ◽  
Victoria Harle ◽  
Peter Repiscak ◽  
William Clark ◽  
Robin Shaw ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Elongation Factor ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Docetaxel Treatment ◽  
Crispr Screen ◽  
Altered Cell

Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit because of emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure. We identified 17 candidate genes whose suppression may enhance the efficacy of docetaxel, with transcription elongation factor A–like 1 (Tceal1) as the top candidate. TCEAL1 function is not fully characterised; it may modulate transcription in a promoter dependent fashion. Suppressed TCEAL1 expression in multiple human prostate cancer cell lines enhanced therapeutic response to docetaxel. Based on gene set enrichment analysis from transcriptomic data and flow cytometry, we confirmed that loss of TCEAL1 in combination with docetaxel leads to an altered cell cycle profile compared with docetaxel alone, with increased subG1 cell death and increased polyploidy. Here, we report the first in vivo genome-wide treatment sensitisation CRISPR screen in prostate cancer, and present proof of concept data on TCEAL1 as a candidate for a combinational strategy with the use of docetaxel.

scholarly journals Gene set enrichment analysis: A genome-wide expression profile-based strategy for discovering functional microRNA–disease relationships

2017 ◽  
Vol 46 (2) ◽  
pp. 596-611 ◽  
Author(s):  
Yin Ni ◽  
Caiyun Song ◽  
Shuqing Jin ◽  
Zhoufeng Chen ◽  
Ming Ni ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Pattern Matching ◽  
Expression Profile ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Gene Set Enrichment ◽  
Genome Wide ◽  
A Genome ◽  
Matching Strategy ◽  
Genome Wide Expression

Objective To explore stable and functional microRNA (miRNA)–disease relationships using a genome-wide expression profile pattern matching strategy. Methods We applied the ranked microarray pattern matching strategy Gene Set Enrichment Analysis to identify miRNA permutations with similar expression patterns to diseases. We also used quantitative reverse transcription PCR to validate the predicted expression levels of miRNAs in three diseases: inflammatory bowel disease (IBD), oesophageal cancer, and colorectal cancer. Results We found that hsa-miR-200 c was upregulated more than 40-fold in oesophageal cancer. The expression of miR-16 and miR-124 was not consistently upregulated in IBD or colorectal cancer. Conclusions Our results suggest that this expression profile matching strategy can be used to identify functional miRNA–disease relationships.

scholarly journals The molecular genetics of hand preference revisited

2018 ◽  
Author(s):  
Carolien G.F. de Kovel ◽  
Clyde Francks
Keyword(s):  
Complex Traits ◽  
Large Population ◽  
Enrichment Analysis ◽  
Hand Preference ◽  
Population Based ◽  
Gene Set Enrichment Analysis ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

AbstractHand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N=331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence implicating any specific candidate variants previously reported. We also found no evidence that genes involved in visceral laterality play a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Within the UK Biobank itself, a significant association implicates the gene MAP2 in handedness.

scholarly journals Gene set enrichment analysis for genome-wide DNA methylation data

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jovana Maksimovic ◽  
Alicia Oshlack ◽  
Belinda Phipson
Keyword(s):  
Dna Methylation ◽  
Enrichment Analysis ◽  
R Package ◽  
Gene Set Enrichment Analysis ◽  
Methylation Array ◽  
Gene Set ◽  
Genome Wide ◽  
Genome Methylation ◽  
Unbiased Gene ◽  
Gene Set Testing

AbstractDNA methylation is one of the most commonly studied epigenetic marks, due to its role in disease and development. Illumina methylation arrays have been extensively used to measure methylation across the human genome. Methylation array analysis has primarily focused on preprocessing, normalization, and identification of differentially methylated CpGs and regions. GOmeth and GOregion are new methods for performing unbiased gene set testing following differential methylation analysis. Benchmarking analyses demonstrate GOmeth outperforms other approaches, and GOregion is the first method for gene set testing of differentially methylated regions. Both methods are publicly available in the missMethyl Bioconductor R package.

Insight Gained from Genome-wide Interaction and Enrichment Analysis on Weight Gain During Citalopram Treatment

2017 ◽  
Vol 41 (S1) ◽  
pp. S163-S163
Author(s):  
H. Corfitsen ◽  
A. Drago
Keyword(s):  
Weight Gain ◽  
Myogenic Differentiation ◽  
Antidepressant Treatment ◽  
Enrichment Analysis ◽  
Molecular Pathways ◽  
Present Contribution ◽  
White Adipocyte ◽  
Antidepressant Treatments ◽  
Molecular Events ◽  
Genome Wide

IntroductionWeight gain is a side effect of pharmacological antidepressant treatments, causing a poorer compliance, increasing the risk of metabolic syndrome and periods of untreated disease.ObjectivesThe ability to precisely prescribe pharmacological treatments based on personal genetic makeups would increase the quality of the current antidepressant treatments.AimsThe molecular pathways enriched during citalopram induced weight gain are identified.Methods643 depressed citalopram treated individuals with available clinical and genome-wide genetic information were investigated in the present contribution in order to identify the molecular pathways that holds the key to weight gain. Statistics were conducted in R environment (Bioconductor and Reactome packages), ANOVA and MANCOVA served when appropriate. Plink was used for genetic analysis in a linux environment.ResultsOne hundred and eleven individuals had their weight increased after treatment with citalopram. The axon guidance (P. adjust = 0.005) and the developmental biology pathway (P. adjust = 0.01) were found to be enriched in genetic variations associated with weight gain.ConclusionsThe development biology pathway includes molecular cascades involved in the regulation of beta-cell development, and the transcriptional regulation of white adipocyte differentiation. A number of variations were harboured by genes whose products are involved in the synthesis of collagen (COL4A3, COL5A1 and ITGA1), activity of the thyroid-hormones (NCOR1 and NCOR2), energy metabolism (ADIPOQ, PPARGC1A) and myogenic differentiation (CDON). A molecular pathway analysis conducted in a sample of depressed patients identifies new candidate genes whose future investigation may grant relevant insights in the molecular events that drive weight gain during antidepressant treatment.

scholarly journals Genome-Wide Effects of Selenium and Translational Uncoupling on Transcription in the Termite Gut Symbiont Treponema primitia

mBio ◽  
2013 ◽  
Vol 4 (6) ◽  
Author(s):  
Eric G. Matson ◽  
Adam Z. Rosenthal ◽  
Xinning Zhang ◽  
Jared R. Leadbetter
Keyword(s):  
Protein Synthesis ◽  
Large Body ◽  
Transcriptional Responses ◽  
Translational Coupling ◽  
Genome Wide ◽  
A Genome ◽  
Protein Encoding ◽  
Termite Gut ◽  
Inhibiting Protein ◽  
Encoding Genes

ABSTRACTWhen prokaryotic cells acquire mutations, encounter translation-inhibiting substances, or experience adverse environmental conditions that limit their ability to synthesize proteins, transcription can become uncoupled from translation. Such uncoupling is known to suppress transcription of protein-encoding genes in bacteria. Here we show that the trace element selenium controls transcription of the gene for the selenocysteine-utilizing enzyme formate dehydrogenase (fdhFSec) through a translation-coupled mechanism in the termite gut symbiontTreponema primitia, a member of the bacterial phylumSpirochaetes. We also evaluated changes in genome-wide transcriptional patterns caused by selenium limitation and by generally uncoupling translation from transcription via antibiotic-mediated inhibition of protein synthesis. We observed that inhibiting protein synthesis inT. primitiainfluences transcriptional patterns in unexpected ways. In addition to suppressing transcription of certain genes, the expected consequence of inhibiting protein synthesis, we found numerous examples in which transcription of genes and operons is truncated far downstream from putative promoters, is unchanged, or is even stimulated overall. These results indicate that gene regulation in bacteria allows for specific post-initiation transcriptional responses during periods of limited protein synthesis, which may depend both on translational coupling and on unclassified intrinsic elements of protein-encoding genes.IMPORTANCEA large body of literature demonstrates that the coupling of transcription and translation is a general and essential method by which bacteria regulate gene expression levels. However, the potential role of noncanonical amino acids in regulating transcriptional output via translational control remains, for the most part, undefined. Furthermore, the genome-wide transcriptional state in response to translational decoupling is not well quantified. The results presented here suggest that the noncanonical amino acid selenocysteine is able to tune transcription of an important metabolic gene via translational coupling. Furthermore, a genome-wide analysis reveals that transcriptional decoupling produces a wide-ranging effect and that this effect is not uniform. These results exemplify how growth conditions that impact translational processivity can rapidly feed back on transcriptional productivity of prespecified groups of genes, providing bacteria with an efficient response to environmental changes.

scholarly journals Genome-wide association analysis of hippocampal volume identifies enrichment of neurogenesis-related pathways

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Emrin Horgusluoglu-Moloch ◽  
◽  
Shannon L. Risacher ◽  
Paul K. Crane ◽  
Derrek Hibar ◽  
...  
Keyword(s):  
Association Analysis ◽  
Adult Neurogenesis ◽  
Enrichment Analysis ◽  
Hippocampal Volume ◽  
Imaging Genetics ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Genome Wide

Abstract Adult neurogenesis occurs in the dentate gyrus of the hippocampus during adulthood and contributes to sustaining the hippocampal formation. To investigate whether neurogenesis-related pathways are associated with hippocampal volume, we performed gene-set enrichment analysis using summary statistics from a large-scale genome-wide association study (N = 13,163) of hippocampal volume from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium and two year hippocampal volume changes from baseline in cognitively normal individuals from Alzheimer’s Disease Neuroimaging Initiative Cohort (ADNI). Gene-set enrichment analysis of hippocampal volume identified 44 significantly enriched biological pathways (FDR corrected p-value < 0.05), of which 38 pathways were related to neurogenesis-related processes including neurogenesis, generation of new neurons, neuronal development, and neuronal migration and differentiation. For genes highly represented in the significantly enriched neurogenesis-related pathways, gene-based association analysis identified TESC, ACVR1, MSRB3, and DPP4 as significantly associated with hippocampal volume. Furthermore, co-expression network-based functional analysis of gene expression data in the hippocampal subfields, CA1 and CA3, from 32 normal controls showed that distinct co-expression modules were mostly enriched in neurogenesis related pathways. Our results suggest that neurogenesis-related pathways may be enriched for hippocampal volume and that hippocampal volume may serve as a potential phenotype for the investigation of human adult neurogenesis.

scholarly journals Gene Expression Profiling of Biological Pathway Alterations by Radiation Exposure

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Kuei-Fang Lee ◽  
Julia Tzu-Ya Weng ◽  
Paul Wei-Che Hsu ◽  
Yu-Hsiang Chi ◽  
Ching-Kai Chen ◽  
...  
Keyword(s):  
Radiation Exposure ◽  
Expression Profiling ◽  
Metabolic Disorders ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Gene Set Enrichment Analysis ◽  
Critical Threshold ◽  
Low Dose Radiation ◽  
A Genome ◽  
Dose Radiation

Though damage caused by radiation has been the focus of rigorous research, the mechanisms through which radiation exerts harmful effects on cells are complex and not well-understood. In particular, the influence of low dose radiation exposure on the regulation of genes and pathways remains unclear. In an attempt to investigate the molecular alterations induced by varying doses of radiation, a genome-wide expression analysis was conducted. Peripheral blood mononuclear cells were collected from five participants and each sample was subjected to 0.5 Gy, 1 Gy, 2.5 Gy, and 5 Gy of cobalt 60 radiation, followed by array-based expression profiling. Gene set enrichment analysis indicated that the immune system and cancer development pathways appeared to be the major affected targets by radiation exposure. Therefore, 1 Gy radioactive exposure seemed to be a critical threshold dosage. In fact, after 1 Gy radiation exposure, expression levels of several genes including FADD, TNFRSF10B, TNFRSF8, TNFRSF10A, TNFSF10, TNFSF8, CASP1, and CASP4 that are associated with carcinogenesis and metabolic disorders showed significant alterations. Our results suggest that exposure to low-dose radiation may elicit changes in metabolic and immune pathways, potentially increasing the risk of immune dysfunctions and metabolic disorders.

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