scholarly journals Sex differences in the human brain transcriptome of cases with schizophrenia

2020 ◽  
Author(s):  
Gabriel E. Hoffman ◽  
Yixuan Ma ◽  
Kelsey S. Montgomery ◽  
Jaroslav Bendl ◽  
Manoj Kumar Jaiswal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Differential Expression ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Age Of Onset ◽  
Differential Expression Analysis ◽  
Gene Expression Signature ◽  
Synaptic Organization ◽  
Expression Signature

AbstractWhile schizophrenia differs between males and females in age of onset, symptomatology and the course of the disease, the molecular mechanisms underlying these differences remain uncharacterized. In order to address questions about the sex-specific effects of schizophrenia, we performed a large-scale transcriptome analysis of RNA-seq data from 437 controls and 341 cases from two distinct cohorts from the CommonMind Consortium. Analysis across the cohorts identifies a reproducible gene expression signature of schizophrenia that is highly concordant with previous work. Differential expression across sex is reproducible across cohorts and identifies X- and Y-linked genes, as well as those involved in dosage compensation. Intriguingly, the sex expression signature is also enriched for genes involved in neurexin family protein binding and synaptic organization. Differential expression analysis testing a sex-by-diagnosis interaction effect did not identify any genome-wide signature after multiple testing corrections. Gene coexpression network analysis was performed to reduce dimensionality and elucidate interactions among genes. We found enrichment of co-expression modules for sex-by-diagnosis differential expression signatures, which were highly reproducible across the two cohorts and involve a number of diverse pathways, including neural nucleus development, neuron projection morphogenesis, and regulation of neural precursor cell proliferation. Overall, our results indicate that the effect size of sex differences in schizophrenia gene expression signatures is small and underscore the challenge of identifying robust sex-by-diagnosis signatures, which will require future analyses in larger cohorts.

The rheumatoid arthritis gene expression signature among women who improve or worsen during pregnancy – a pilot study

2020 ◽  
pp. jrheum.201128
Author(s):  
Amogh Pathi ◽  
Matthew Wright ◽  
Mette Kiel Smed ◽  
J. Lee Nelson ◽  
Jørn Olsen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Disease Activity ◽  
Differential Expression ◽  
Differential Expression Analysis ◽  
Gene Expression Signature ◽  
Differentially Expressed ◽  
Expression Signature ◽  
Healthy Women ◽  
Gene Expression Signatures

Objective To assess whether gene expression signatures associated with rheumatoid arthritis (RA) before pregnancy differ between women who improve or worsen during pregnancy, and determine whether these expression signatures are altered during pregnancy when RA improves or worsens. Methods Clinical data and blood samples were collected before pregnancy (T0) and at the third trimester (T3) from 11 RA and 5 healthy women. RA disease activity was assessed using the Clinical Disease Activity Index (CDAI). At each time-point, RA-associated gene expression signatures were identified using differential expression analysis of RNA sequencing profiles between RA and healthy women. Results Of the women with RA, 6 improved by T3 (RAimproved), 3 worsened (RAworsened) and 2 were excluded. At T0, mean CDAI scores were similar in both groups (RAimproved: 11.2±9.8; RAworsened: 13.8±6.7; Wilcoxon-rank test: p=0.6). In the RAimproved group, 89 genes were differentially expressed at T0 (q<0.05 and fold-change (FC)≥2) compared to healthy women. When RA improved at T3, 65 of 89 (73%) of these no longer displayed RA-associated expression. In the RAworsened group, a largely different RA gene expression signature (429 genes) was identified at T0. When RA disease activity worsened at T3, 207 of 429 (48%) lost their differential expression, while an additional 157 genes became newly differentially expressed. Conclusion In our pilot dataset, pre-pregnancy RA expression signatures differed between women who subsequently improved or worsened during pregnancy, suggesting that inherent genomic differences perhaps influence how pregnancy impacts disease activity. Further, these RA signatures were altered during pregnancy, as disease activity changed.

scholarly journals Distinct molecular etiologies of male and female hepatocellular carcinoma

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Heini M. Natri ◽  
Melissa A. Wilson ◽  
Kenneth H. Buetow
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Sex Differences ◽  
Differential Expression ◽  
Differential Expression Analysis ◽  
Regulation Of Transcription ◽  
Male And Female ◽  
Differential Effects ◽  
Pathway Enrichment

Abstract Background Sex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC. Methods Here, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort using combined and sex-stratified differential expression and eQTL analyses. Results By using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression. Conclusions Sex-stratified analyses detect sex-specific molecular etiologies of HCC. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.

A gene expression signature for insulin resistance

2011 ◽  
Vol 43 (3) ◽  
pp. 110-120 ◽  
Author(s):  
Nicky Konstantopoulos ◽  
Victoria C. Foletta ◽  
David H. Segal ◽  
Katherine A. Shields ◽  
Andrew Sanigorski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Large Scale ◽  
Gene Expression Signature ◽  
Channel Blockers ◽  
Expression Signature ◽  
Insulin Resistant ◽  
Novel Strategy

Insulin resistance is a heterogeneous disorder caused by a range of genetic and environmental factors, and we hypothesize that its etiology varies considerably between individuals. This heterogeneity provides significant challenges to the development of effective therapeutic regimes for long-term management of type 2 diabetes. We describe a novel strategy, using large-scale gene expression profiling, to develop a gene expression signature (GES) that reflects the overall state of insulin resistance in cells and patients. The GES was developed from 3T3-L1 adipocytes that were made “insulin resistant” by treatment with tumor necrosis factor-α (TNF-α) and then reversed with aspirin and troglitazone (“resensitized”). The GES consisted of five genes whose expression levels best discriminated between the insulin-resistant and insulin-resensitized states. We then used this GES to screen a compound library for agents that affected the GES genes in 3T3-L1 adipocytes in a way that most closely resembled the changes seen when insulin resistance was successfully reversed with aspirin and troglitazone. This screen identified both known and new insulin-sensitizing compounds including nonsteroidal anti-inflammatory agents, β-adrenergic antagonists, β-lactams, and sodium channel blockers. We tested the biological relevance of this GES in participants in the San Antonio Family Heart Study ( n = 1,240) and showed that patients with the lowest GES scores were more insulin resistant (according to HOMA_IR and fasting plasma insulin levels; P < 0.001). These findings show that GES technology can be used for both the discovery of insulin-sensitizing compounds and the characterization of patients into subtypes of insulin resistance according to GES scores, opening the possibility of developing a personalized medicine approach to type 2 diabetes.

scholarly journals Sex differences in gene expression patterns associated with the APOE4 allele

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 387
Author(s):  
Michelle Hsu ◽  
Mehek Dedhia ◽  
Wim Crusio ◽  
Anna Delprato
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Age Of Onset ◽  
Late Onset ◽  
Expression Patterns ◽  
Differential Expression Analysis ◽  
Negative Control ◽  
Gene Expression Patterns ◽  
Dependent Manner ◽  
Examine Gene Expression

Background: The APOE gene encodes apolipoprotein ε (ApoE), a protein that associates with lipids to form lipoproteins that package and traffic cholesterol and lipids through the bloodstream. There are at least three different alleles of the APOE gene: APOE2, APOE3, and APOE4. The APOE4 allele increases an individual's risk for developing late-onset Alzheimer disease (AD) in a dose-dependent manner. Sex differences have been reported for AD susceptibility, age of onset, and symptom progression, with females being more affected than males. Methods: In this study, we use a systems biology approach to examine gene expression patterns in the brains of aged female and male individuals who are positive for the APOE4 allele in order to identify possible sex-related differences that may be relevant to AD. Results: Based on correlation analysis, we identified a large number of genes with an expression pattern similar to that of APOE in APOE4-positive individuals. The number of these genes was much higher in APOE4-positive females than in APOE4-positive males, who in turn had more of such genes than APOE4-negative control groups. Conclusions: Profiling of these genes using Gene Ontology (GO) term classification, pathway enrichment, and differential expression analysis supports the idea of a transcriptional role of APOE with respect to sex differences and AD.

scholarly journals Distinct molecular etiologies of male and female hepatocellular carcinoma

2019 ◽  
Author(s):  
Heini M Natri ◽  
Melissa A Wilson ◽  
Kenneth H Buetow
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Sex Differences ◽  
Differential Expression ◽  
Differential Expression Analysis ◽  
Regulation Of Transcription ◽  
Male And Female ◽  
Differential Effects ◽  
Pathway Enrichment

Abstract Background: Sex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC. Methods: Here, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort using combined and sex-stratified differential expression and eQTL analyses. Results: By using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, 305 PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression. Conclusions: Sex-stratified analyses detect sex-specific molecular etiologies of HCC. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.

scholarly journals Distinct molecular etiologies of male and female hepatocellular carcinoma

2019 ◽  
Author(s):  
Heini M Natri ◽  
Melissa A Wilson ◽  
Kenneth H Buetow
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Sex Differences ◽  
Differential Expression ◽  
Differential Expression Analysis ◽  
Regulation Of Transcription ◽  
Male And Female ◽  
Differential Effects ◽  
Pathway Enrichment

Abstract Background: Sex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC. Methods: Here, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort using combined and sex-stratified differential expression and eQTL analyses. Results: By using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, 305 PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression. Conclusions: Sex-stratified analyses detect sex-specific molecular etiologies of HCC. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.

scholarly journals Large-scale integrated analysis of ovarian cancer tumors and cell lines identifies an individualized gene expression signature for predicting response to platinum-based chemotherapy

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Jie Sun ◽  
Siqi Bao ◽  
Dandan Xu ◽  
Yan Zhang ◽  
Jianzhong Su ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Cell Lines ◽  
Large Scale ◽  
Gene Expression Signature ◽  
Integrated Analysis ◽  
Chemotherapy Response ◽  
Expression Signature ◽  
Platinum Based Chemotherapy ◽  
Response To Chemotherapy

Abstract Heterogeneity in chemotherapeutic response is directly associated with prognosis and disease recurrence in patients with ovarian cancer (OvCa). Despite the significant clinical need, a credible gene signature for predicting response to platinum-based chemotherapy and for guiding the selection of personalized chemotherapy regimens has not yet been identified. The present study used an integrated approach involving both OvCa tumors and cell lines to identify an individualized gene expression signature, denoted as IndividCRS, consisting of 16 robust chemotherapy-responsive genes for predicting intrinsic or acquired chemotherapy response in the meta-discovery dataset. The robust performance of this signature was subsequently validated in 25 independent tumor datasets comprising 2215 patients and one independent cell line dataset, across different technical platforms. The IndividCRS was significantly correlated with the response to platinum therapy and predicted the improved outcome. Moreover, the IndividCRS correlated with homologous recombination deficiency (HRD) and was also capable of discriminating HR-deficient tumors with or without platinum-sensitivity for guiding HRD-targeted clinical trials. Our results reveal the universality and simplicity of the IndividCRS as a promising individualized genomic tool to rapidly monitor response to chemotherapy and predict the outcome of patients with OvCa.

Prediction of metastatic castrate-resistant prostate cancer response to abiraterone or enzalutamide by a baseline blood-based CTC gene expression signature.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16529-e16529
Author(s):  
Michael Joseph Lariviere ◽  
Naomi B. Haas ◽  
Yauheniya Cherkas ◽  
Karl Nielsen ◽  
Brad Foulk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Prospective Study ◽  
Molecular Mechanisms ◽  
Gene Expression Signature ◽  
Blood Samples ◽  
Expression Signature ◽  
Number Of Patients ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

e16529 Background: Prostate cancer is the most common cancer in men in the U.S., with 30% 5-year overall survival (OS) for patients (pts) with metastases. To take a precision medicine approach to the management of metastatic castrate-resistant prostate cancer (mCRPC), we developed a blood circulating tumor cell (CTC)-based test to identify mCRPC pts most likely to benefit from abiraterone (abi) or enzalutamide (enza). Methods: In this multi-institution prospective study, men with mCRPC were enrolled prior to starting abi (1,000 mg/d plus prednisone 10 mg/d) or enza (160 mg/d). At baseline (BL), 12 w, and progression, blood samples were collected for CellSearch-based CTC enumeration and qPCR-based gene expression analysis. Results: 69 pts (median age 68 y [50-82]) received abi (n = 25) or enza (n = 44) and had evaluable blood samples. Consistent with prior publications, among 43 pts with BL CTC > 0, clearance of detectable CTCs (BL CTCs > 0 and 12 w CTCs = 0), was achieved in 24 patients (55.8%), and was associated with greater median OS (31 mo vs. 18 mo, log-rank p = 0.03). The 43 pts with BL CTC > 0 were then randomly divided into training (n = 31) and validation (n = 12) sets. Baseline gene expression data for the training set was used to develop a model to predict CTC clearance, starting with a panel of 141 expressed genes/isoforms including those associated with prostate cancer. Of the models tested, random forest yielded the best performance, with respective training and validation set sensitivity of 0.7 and 1, specificity 0.75 and 0.71, AUC 0.88 and 0.91. Top genes identified include those previously associated with disease – HOXB13, ESRP2, KLK3, GRHL2, and KRT19, among others. Conclusions: A gene expression signature from a baseline blood sample with CellSearch-enriched CTCs can predict clearance of detectable CTCs in response to abi/enza with high AUC and may give insight into molecular mechanisms of response. A prospective study with a larger number of patients will be required to further validate our findings. Ultimately, this blood test has the potential to select the patients most likely to benefit from second-generation antiandrogen vs. non-hormonal systemic treatment.

scholarly journals Identification of a Gene Signature Associated to Treatment Response to Palbociclib in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5666-5666
Author(s):  
Angelique Bruyer ◽  
Alboukadel Kassambara ◽  
Paul Anziani ◽  
Donia El Bahlagui ◽  
Nicolas Robert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Multiple Myeloma ◽  
Rna Sequencing ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Gene Expression Signature ◽  
G1 Arrest ◽  
Expression Signature

Abstract Background: Inpatients with relaspsed/refractoryMultiple Myeloma (MM), outcomes are far from optimal, especially in patients refractory to current treatments Recent studies and clinical trials have highlighted the therapeutic potential of Palbociclib, a CDK4/6 inhibitor, in various cancers including MM. Deregulation of CDK4/6 is involved in the loss of cell cycle control in MM. Response to Palbociclib combined with bortezomib and dexamethasone was acquired in 20% of the relapsed/refractory MM patients, suggesting that biomarkers to identify patients that could benefit from this treatment are needed. Additional studies are required to understand the biological pathways associated with sensitivity or resistance of MM cells to Palbociclib. Methods: 14 human MM cell lines and 12 primary MM samples were tested for response to Palbociclib treatment. The concentration required to inhibit growth by 50% (IC50) was calculated. Gene expression signature associated with multiple myeloma response to Palbociclib, as well as, genes deregulated by the treatment have been analyzed using microarray and RNA-sequencing methods. Results: Palbociclib had an heterogeneous in vitro activity among the 14 human myeloma cell lines tested, which aggregated into three groups based on the distribution of the IC50 values: sensitive (n = 5, IC50: 0.2 - 0.3µM), intermediate (n = 3, IC50: 0.5 - 0.7µM) or more resistant group (n = 6, IC50: 0.9 - 2.4µM). The same holds true when testing the Palbociclib on primary multiple myeloma samples. The evaluation of the Palbociclib effect on cell cycle progression and the induction of the apoptosis, reveals that Palbociclib is essentially cytostatic, inducing prolonged G1 arrest in sensitive cell lines with a strong reduction of the percentage of cells in S phase. To better understand the molecular mechanisms associated with Palbociclib response, we identified a gene expression signature correlated with the response in both MM cell lines and primary myeloma cells from patients. Additionally, we have analyzed differentially expressed genes after Palbociclib treatment in human MM cell lines using RNA sequencing (n = 4). The physiological role of the downregulated genes after Palbociclib treatment is associated with cell cycle, mitosis and E2F mediated regulation of DNA replication. Significantly upregulated genes, after Palbociclib treatment, were enriched in genes encoding proteins involved in glutathione synthesis and recycling, and biological oxidations. Conclusion: Altogether, our data demonstrated a high heterogeneity in the response of MM cells to Palbociclib. We identified a gene expression signature associated with Palbociclib response in MM. These genes could help to identify MM patients that could benefit from Palbociclib treatment and provide novel targets for efficient combination therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Single cell analysis reveals stochastic cell-to-cell variation in stress response and senescence program

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 1055-1055
Author(s):  
Nikolay Burnaevskiy ◽  
Alexander Mendenhall
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Single Cell ◽  
Large Scale ◽  
Single Cell Analysis ◽  
Human Fibroblasts ◽  
Gene Expression Signature ◽  
Controlled Environment ◽  
Proliferating Cells ◽  
Expression Signature

Abstract Cells have various means to respond to molecular stress. Upon stress, proliferating cells can adopt different fates, e.g. commit to apoptosis, go into senescence or recover from stress and resume proliferation, depending on severity of the stress. Proper balance between these modes of response is critical for maintaining tissue homeostasis with age, as both exacerbated and insufficient response can result in pathology. Remarkably, even genetically identical cells of the same type in the controlled environment can exhibit a spectrum of responses to the same stress challenge. We hypothesized that analyzing response of individual cells in controlled environment can help better understand the mechanisms that ensure a balanced response to molecular stress. We used large scale single cell RNA-sequencing to analyze response of individual human fibroblasts to oxidative stress. Consistent with various fates adopted by individual cells upon stress, we observed different transcriptional signatures, that correspond to those fates. Surprisingly, when we specifically analyzed ß-gal+ senescent cells, we still observed transcriptional heterogeneity, with only a subset of cells exhibiting pro-senescent transcriptional signature (e.g. activated p53 and TNF-a pathways) while another subset exhibits a gene expression signature of senescent-like arrest. Hence, we find that in addition to known stress-related fates (apoptosis, senescence, recovery) senescence-like response is heterogeneous with only subset of cells exhibiting expected pro-senescent gene expression signature. Further characterization of heterogeneity of stress response and senescent-like fates will help better understand the mechanisms of homeostatic control in the face of molecular stress and aging.

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