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Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants.

ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depression. However, the link between inhibition of serotonin reuptake and remission from depression remains controversial: in spite of the rapid onset of serotonin reuptake inhibition, remission from depression takes several weeks, presumably reflecting synaptogenesis/neurogenesis and neuronal rewiring. We compared genome-wide expression profiles of human lymphoblastoid cell lines from unrelated individuals following treatment with 1 ?M paroxetine for 21 days with untreated control cells and examined which genes and microRNAs (miRNAs) showed the most profound and consistent expression changes. ITGB3, coding for integrin beta-3, showed the most consistent altered expression (1.92-fold increase, P=7.5 × 10(-8)) following chronic paroxetine exposure. Using genome-wide miRNA arrays, we observed a corresponding decrease in the expression of two miRNAs, miR-221 and miR-222, both predicted to target ITGB3. ITGB3 is crucial for the activity of the serotonin transporter (SERT), the drug target of SSRIs. Moreover, it is presumably required for the neuronal guidance activity of CHL1, whose expression was formerly identified as a tentative SSRI response biomarker. Further genes whose expression was significantly modulated by chronic paroxetine are also implicated in neurogenesis. Surprisingly, the expression of SERT or serotonin receptors was not modified. Our findings implicate ITGB3 in the mode of action of SSRI antidepressants and provide a novel link between CHL1 and the SERT. Our observations suggest that SSRIs may relieve depression primarily by promoting neuronal synaptogenesis/neurogenesis rather than by modulating serotonin neurotransmission per se.

SUBMITTER: Oved K

PROVIDER: S-EPMC3818017 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants.

Oved K K Morag A A Pasmanik-Chor M M Rehavi M M Shomron N N Gurwitz D D

Translational psychiatry 20131015

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depression. However, the link between inhibition of serotonin reuptake and remission from depression remains controversial: in spite of the rapid onset of serotonin reuptake inhibition, remission from depression takes several weeks, presumably reflecting synaptogenesis/neurogenesis and neuronal rewiring. We compared genome-wide expression profiles of human lymphoblastoid cell lines from unrelated individuals f ...[more]

PMID: 24129413

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Project description:BackgroundExpression level of many genes shows abundant natural variation in human populations. The variations in gene expression are believed to contribute to phenotypic differences. Emerging evidence has shown that microRNAs (miRNAs) are one of the key regulators of gene expression. However, past studies have focused on the miRNA target genes and used loss- or gain-of-function approach that may not reflect natural association between miRNA and mRNAs.Methodology/principal findingsTo examine miRNA regulatory effect on global gene expression under endogenous condition, we performed pair-wise correlation coefficient analysis on expression levels of 366 miRNAs and 14,174 messenger RNAs (mRNAs) in 90 immortalized lymphoblastoid cell lines, and observed significant correlations between the two species of RNA transcripts. We identified a total of 7,207 significantly correlated miRNA-mRNA pairs (false discovery rate q<0.01). Of those, 4,085 pairs showed positive correlations while 3,122 pairs showed negative correlations. Gene ontology analyses on the miRNA-correlated genes revealed significant enrichments in several biological processes related to cell cycle, cell communication and signal transduction. Individually, each of three miRNAs (miR-331, -98 and -33b) demonstrated significant correlation with the genes in cell cycle-related biological processes, which is consistent with important role of miRNAs in cell cycle regulation.Conclusions/significanceThis study demonstrates feasibility of using naturally expressed transcript profiles to identify endogenous correlation between miRNA and miRNA. By applying this genome-wide approach, we have identified thousands of miRNA-correlated genes and revealed potential role of miRNAs in several important cellular functions. The study results along with accompanying data sets will provide a wealth of high-throughput data to further evaluate the miRNA-regulated genes and eventually in phenotypic variations of human populations.

Project description:BackgroundEpidemiological studies of DNA methylation profiles may uncover the molecular mechanisms through which genetic and environmental factors contribute to the risk of multifactorial diseases. There are two types of commonly used DNA bioresources, peripheral blood cells (PBCs) and EBV-transformed lymphoblastoid cell lines (LCLs), which are available for genetic epidemiological studies. Therefore, to extend our knowledge of the difference in DNA methylation status between LCLs and PBCs is important in human population studies that use these DNA sources to elucidate the epigenetic risks for multifactorial diseases. We analyzed the methylation status of the autosomes for 192 and 92 DNA samples that were obtained from PBCs and LCLs, respectively, using a human methylation 450 K array. After excluding SNP-associated methylation sites and low-call sites, 400,240 sites were subjected to analysis using a generalized linear model with cell type, sex, and age as the independent variables.ResultsWe found that the large proportion of sites showed lower methylation levels in LCLs compared with PBCs, which is consistent with previous reports. We also found that significantly different methylation sites tend to be located on the outside of the CpG island and in a region relatively far from the transcription start site. Additionally, we observed that the methylation change of the sites in the low-CpG promoter region was remarkable. Finally, it was shown that the correlation between the chronological age and ageing-associated methylation sites in ELOVL2 and FHL2 in the LCLs was weaker than that in the PBCs.ConclusionsThe methylation levels of highly methylated sites of the low-CpG-density promoters in PBCs decreased in the LCLs, suggesting that the methylation sites located in low-CpG-density promoters could be sensitive to demethylation in LCLs. Despite being generated from a single cell type, LCLs may not always be a proxy for DNA from PBCs in studies of epigenome-wide analysis attempting to elucidate the role of epigenetic change in disease risks.

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Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants.

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Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants.

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