Blood Expression Profiles Research Articles

Inflammatory gene expression profiling in peripheral blood from patients with Alzheimer's disease reveals key pathways and hub genes with potential diagnostic utility: a preliminary study.

BackgroundAlzheimer’s disease (AD) is an age-related neurodegenerative disease caused by central nervous system disorders. Late-onset Alzheimer disease (LOAD) is the most common neurodegenerative disorder worldwide. Differences at the expression level of certain genes, resulting from either genetic variations or environmental interactions, might be one of the mechanisms underlying differential risks for developing AD. Peripheral blood genome transcriptional profiling may provide a powerful and minimally invasive tool for the identification of novel targets beyond Aβ and tau for AD research.MethodsThis preliminary study explores molecular pathogenesis of LOAD-related inflammation through next generation sequencing, to assess RNA expression profiles in peripheral blood from five patients with LOAD and 10 healthy controls.ResultsThe analysis of RNA expression profiles revealed 94 genes up-regulated and 147 down-regulated. Gene function analysis, including Gene Ontology (GO) and KOBAS-Kyoto Encyclopedia of DEGs and Genomes (KEGG) pathways indicated upregulation of interferon family (INF) signaling, while the down-regulated genes were mainly associated with the cell cycle process. KEGG metabolic pathways mapping showed gene expression alterations in the signaling pathways of JAK/STAT, chemokines, MAP kinases and Alzheimer disease. The results of this preliminary study provided not only a comprehensive picture of gene expression, but also the key processes associated with pathology for the regulation of neuroinflammation, to improve the current mechanisms to treat LOAD.

Quantitative analysis of the blood transcriptome of young healthy pigs and its relationship with subsequent disease resilience

BackgroundDisease resilience, which is the ability of an animal to maintain performance under disease, is important for pigs in commercial herds, where they are exposed to various pathogens. Our objective was to investigate population-level gene expression profiles in the blood of 912 healthy F1 barrows at ~ 27 days of age for associations with performance and health before and after their exposure to a natural polymicrobial disease challenge at ~ 43 days of age.ResultsMost significant (q < 0.20) associations of the level of expression of individual genes in blood of young healthy pigs were identified for concurrent growth rate and subjective health scores prior to the challenge, and for mortality, a combined mortality-treatment trait, and feed conversion rate after the challenge. Gene set enrichment analyses revealed three groups of gene ontology biological process terms that were related to disease resilience: 1) immune and stress response-related terms were enriched among genes whose increased expression was unfavorably associated with both pre- and post-challenge traits, 2) heme-related terms were enriched among genes that had favorable associations with both pre- and post-challenge traits, and 3) terms related to protein localization and viral gene expression were enriched among genes that were associated with reduced performance and health traits after but not before the challenge.ConclusionsGene expression profiles in blood from young healthy piglets provide insight into their performance when exposed to disease and other stressors. The expression of genes involved in stress response, heme metabolism, and baseline expression of host genes related to virus propagation were found to be associated with host response to disease.

Immune response in Santa Inês sheep during Fasciola hepatica infection

In the present study, we describe the proliferative response and the IFN-γ, IL-10, IL-4 cytokine expression profiles in peripheral blood, and IgG production, after the experimental infection of Santa Inês sheep with 250 Fasciola hepatica metacercariae that were evaluated at 60 and 210 days post-infection(dpi). The cytokine expression profile at 60 dpi was characterized by the production of IFN-γ and IL-10, which is indicative of an initial mixed Th1/Th2 response. The modulation of the response occurred at 210 dpi with a predominance of IL-10 and IL-4 over IFN-γ. Mononuclear cells from peripheral blood stimulated with F. hepatica antigen exhibited proliferative capacity at 60 dpi, whereas the response was consistent with modulation from Th1 to Th2 in the chronic phase. The IgG antibody response was more marked at 60 days than at 210 dpi, confirming the mixed-response profile. The late modulation of the T lymphocyte response in association with the predominance of IL-10 and IL-4 at 210 dpi suggests the involvement of these cytokines after the establishment of the parasites in the bile ducts. The transition from a mixed to a regulatory response in the chronic phase was also accompanied by a reduced number of eggs per gram of feces.

Analysis of immune cell components and immune-related gene expression profiles in peripheral blood of patients with type 1 diabetes mellitus

BackgroundType 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by severe loss of pancreatic β cells. Immune cells are key mediators of β cell destruction. This study attempted to investigate the role of immune cells and immune-related genes in the occurrence and development of T1DM.MethodsThe raw gene expression profile of the samples from 12 T1DM patients and 10 normal controls was obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by Limma package in R. The least absolute shrinkage and selection operator (LASSO)—support vector machines (SVM) were used to screen the hub genes. CIBERSORT algorithm was used to identify the different immune cells in distribution between T1DM and normal samples. Correlation of the hub genes and immune cells was analyzed by Spearman, and gene-GO-BP and gene-pathway interaction networks were constructed by Cytoscape plug-in ClueGO. Receiver operating characteristic (ROC) curves were used to assess diagnostic value of genes in T1DM.ResultsThe 50 immune-related DEGs were obtained between the T1DM and normal samples. Then, the 50 immune-related DEGs were further screened to obtain the 5 hub genes. CIBERSORT analysis revealed that the distribution of plasma cells, resting mast cells, resting NK cells and neutrophils had significant difference between T1DM and normal samples. Natural cytotoxicity triggering receptor 3 (NCR3) was significantly related to the activated NK cells, M0 macrophages, monocytes, resting NK cells, and resting memory CD4+ T cells. Moreover, tumor necrosis factor (TNF) was significantly associated with naive B cell and naive CD4+ T cell. NCR3 [Area under curve (AUC) = 0.918] possessed a higher accuracy than TNF (AUC = 0.763) in diagnosis of T1DM.ConclusionsThe immune-related genes (NCR3 and TNF) and immune cells (NK cells) may play a vital regulatory role in the occurrence and development of T1DM, which possibly provide new ideas and potential targets for the immunotherapy of diabetes mellitus (DM).

Circulating exosomal miR-363-5p inhibits lymph node metastasis by downregulating PDGFB and serves as a potential noninvasive biomarker for breast cancer.

Sentinel lymph node (LN) biopsy is currently the standard procedure for clinical LN‐negative breast cancer (BC) patients but it is prone to false‐negative results and complications. Thus, an accurate noninvasive approach for LN staging is urgently needed in clinical practice. Here, circulating exosomal microRNA (miRNA) expression profiles in peripheral blood from BC patients and age‐matched healthy women were obtained and analyzed. We identified an exosomal miRNA, miR‐363‐5p, that was significantly downregulated in exosomes from plasma of BC patients with LN metastasis which exhibited a consistent decreasing trend in tissue samples from multiple independent datasets. Plasma exosomal miR‐363‐5p achieved high diagnostic performance in distinguishing LN‐positive patients from LN‐negative patients. The high miR‐363‐5p expression level was significantly correlated with improved overall survival. Functional assays demonstrated that exosomal miR‐363‐5p modulates platelet‐derived growth factor (PDGF) signaling activity by targeting PDGFB to inhibit cell proliferation and migration. Our study revealed, for the first time, plasma exosomal miR‐363‐5p plays a tumor suppressor role in BC and has the potential for noninvasive LN staging and prognosis prediction of BC.

Impact of aging on gene expression response to x-ray irradiation using mouse blood

As a radiation biodosimetry tool, gene expression profiling is being developed using mouse and human peripheral blood models. The impact of dose, dose-rate, and radiation quality has been studied with the goal of predicting radiological tissue injury. In this study, we determined the impact of aging on the gene expression profile of blood from mice exposed to radiation. Young (2 mo) and old (21 mo) male mice were irradiated with 4 Gy x-rays, total RNA was isolated from whole blood 24 h later, and subjected to whole genome microarray analysis. Pathway analysis of differentially expressed genes revealed young mice responded to x-ray exposure by significantly upregulating pathways involved in apoptosis and phagocytosis, a process that eliminates apoptotic cells and preserves tissue homeostasis. In contrast, the functional annotation of senescence was overrepresented among differentially expressed genes from irradiated old mice without enrichment of phagocytosis pathways. Pathways associated with hematologic malignancies were enriched in irradiated old mice compared with irradiated young mice. The fibroblast growth factor signaling pathway was underrepresented in older mice under basal conditions. Similarly, brain-related functions were underrepresented in unirradiated old mice. Thus, age-dependent gene expression differences should be considered when developing gene signatures for use in radiation biodosimetry.

De-coding genetic risk variants in type 1 diabetes.

The conceptual basis for a genetic predisposition underlying the risk for developing type 1 diabetes (T1D) predates modern human molecular genetics. Over half of the genetic risk has been attributed to the human leukocyte antigen (HLA) class II gene region and to the insulin (INS) gene locus - both thought to confer direction of autoreactivity and tissue specificity. Notwithstanding, questions still remain regarding the functional contributions of a vast array of minor polygenic risk variants scattered throughout the genome that likely influence disease heterogeneity and clinical outcomes. Herein, we summarize the available literature related to the T1D-associated coding variants defined at the time of this review, for the genes PTPN22, IFIH1, SH2B3, CD226, TYK2, FUT2, SIRPG, CTLA4, CTSH and UBASH3A. Data from genotype-selected human cohorts are summarized, and studies from the non-obese diabetic (NOD) mouse are presented to describe the functional impact of these variants in relation to innate and adaptive immunity as well as to β-cell fragility, with expression profiles in tissues and peripheral blood highlighted. The contribution of each variant to progression through T1D staging, including environmental interactions, are discussed with consideration of how their respective protein products may serve as attractive targets for precision medicine-based therapeutics to prevent or suspend the development of T1D.

Temporal microRNA expression profile of pig peripheral blood during postnatal development

Gene expression profiles of blood can reflect the physiopathologic status of the immune system. The dynamic microRNA (miRNA) expression profiles of peripheral blood from pigs at different developmental stages, and how differential expression of miRNAs might relate to immune system development, are unknown. In this study, peripheral blood samples taken at five developmental stages were used to construct 15 miRNA libraries (three biological replicates/stage): 0 days (newborn), 30 days (weaning), 60 days (weaned), and 180 and 360 days (puberty). We identified 295 known mature miRNAs. Hierarchical clustering of the miRNA expression profile showed significant differences between individuals at the neonatal and postnatal stages. Functional enrichment analysis revealed that miRNAs differentially expressed between pairwise comparisons of the developmental stages were over-represented in immune-related pathways such as toll-like receptor signaling. The time-course of expression of the over-representated miRNAs exhibited a pattern of steady decline over time, for both the complete miRNA compendium and immune-related miRNAs. We identified six marker miRNAs that were highly negatively correlated with chronologic age and enriched for genes involved in immune-related pathways. This study of a peripheral blood miRNA transcriptome offers insight into immune system development in swine and provides a resource for pig genome annotation.

Identifying RNA Biomarkers and Molecular Pathways Involved in Multiple Subtypes of Uveitis

Uveitis is a heterogeneous collection of diseases. We tested the hypothesis that despite the diversity of uveitides, there could be common mechanisms shared by multiple subtypes, and that evidence of these common mechanisms may be detected as gene expression profiles in whole blood. Cohort study. Ninety subjects with uveitis including axial spondyloarthritis (n=17), sarcoidosis (n=13), inflammatory bowel disease (n=12), tubulointerstitial nephritis with uveitis (n=10), or idiopathic uveitis (n=38) as well as 18 healthy controls were enrolled, predominantly at Oregon Health & Science University. RNA-Seq data generated from peripheral, whole blood identified 19,859 unique transcripts. We analyzed gene expression pathways via Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO). We validated our list of upregulated genes by comparison to a previously published study on peripheral blood gene expression among 50 subjects with diverse forms of uveitis. Both the Kyoto Encyclopedia of Genes and Genomes and GO analysis identified multiple shared pathways or GO terms with a P value of <.0001. Almost all pathways related to the immune response and/or response to an infection. A total of 119 individual transcripts were upregulated by at least 1.5-fold and false discovery rate <.05, and 61 were downregulated by similar criteria. Comparing mRNA from our study with a false discovery rate <.05 and the prior report, we identified 10 common gene transcripts: ICAM1, IL15RA, IL15, IRF1, IL10RB, GSK3A, TYK2, MEF2A, MEF2B, and MEF2D. Many forms of uveitis share overlapping mechanisms. These data support the concept that a single therapeutic approach could benefit diverse forms of this disease.

Classification of Patients With Sepsis According to Immune Cell Characteristics: A Bioinformatic Analysis of Two Cohort Studies

Background: Sepsis is well-known to alter innate and adaptive immune responses for sustained periods after initiation by an invading pathogen. Identification of immune cell characteristics may shed light on the immune signature of patients with sepsis and further indicate the appropriate immune-modulatory therapy for distinct populations. Therefore, we aimed to establish an immune model to classify sepsis into different immune endotypes via transcriptomics data analysis of previously published cohort studies.Methods: Datasets from two observational cohort studies that included 585 consecutive sepsis patients admitted to two intensive care units were downloaded as a training cohort and an external validation cohort. We analyzed genome-wide gene expression profiles in blood from these patients by using machine learning and bioinformatics.Results: The training cohort and the validation cohort had 479 and 106 patients, respectively. Principal component analysis indicated that two immune subphenotypes associated with sepsis, designated the immunoparalysis endotype, and immunocompetent endotype, could be distinguished clearly. In the training cohort, a higher cumulative 28-day mortality was found in patients classified as having the immunoparalysis endotype, and the hazard ratio was 2.32 (95% CI: 1.53–3.46 vs. the immunocompetent endotype). External validation further demonstrated that the present model could categorize sepsis into the immunoparalysis and immunocompetent type precisely and efficiently. The percentages of 4 types of immune cells (M0 macrophages, M2 macrophages, naïve B cells, and naïve CD4 T cells) were significantly associated with 28-day cumulative mortality (P < 0.05).Conclusion: The present study developed a comprehensive tool to identify the immunoparalysis endotype and immunocompetent status in hospitalized patients with sepsis and provides novel clues for further targeting of therapeutic approaches.

The SLC25A42 Transcript Is a Biomarker for Fetal Reprogramming in Response to Placental Insufficiency in Preterm Newborns Under 32 Weeks Gestation—A Pilot Study

Introduction: Timing of medical delivery of preterm newborns exposed to placental insufficiency is largely determined by umbilical artery blood flow and maternal clinical manifestations. There is a lack of tools to properly assess fetal body response to placental insufficiency before or upon delivery. Yet, short- and long-term comorbidities associated with placental insufficiency and the consequential intrauterine growth restriction may be a result of fetal response following prolonged stress. This study aims to establish a procedure to investigate fetal/neonatal transcriptional response to placental insufficiency as part of an initiative to identify cost-effective biomarkers for assessing fetal response to placental insufficiency.Methods: A prospective pilot study involving newborns with birth gestation <32 weeks was conducted to compare gene expression profiles in whole blood collected at birth among three clinically distinct groups - preeclampsia without placental insufficiency (PE), placental insufficiency (PI), and non-PE/PI groups.Results: Whole blood from 11, 3, and 6 newborns in the non-PE/PI, PE, and PI groups were obtained. A transcriptome analysis found that the majority of the genes were downregulated in the PI group, suggesting global transcriptional inactivation. Intriguingly, SLC25A42, which encodes a mitochondrial transporter for coenzyme A and adenosine-3′,5′-diphosphate, was significantly upregulated in the PI group.Conclusion: Transcriptional biomarkers for assessing fetal response to placental insufficiency may provide a useful tool to better understand the pathophysiology of fetal reprogramming in response to placental insufficiency. The validity and the role of SLC25A42, as well as its correlation with short- and long-term neonatal outcomes, warrants further investigation.

Circulating circular RNAs profiles associated with type 1 diabetes.

Circular RNAs (circRNAs) have recently been shown to exert important effects in human diseases. However, the roles of circRNAs in type 1 diabetes (T1D) are largely unknown. This study is to identify the circRNA expression profiles in the peripheral blood of patients with T1D and predict their potential regulatory mechanisms and coding potential. CircRNA expression profiles were detected by Arraystar human circRNA microarray. With real-time PCR validation, multiple bioinformatics approaches were used to explore their biological functions, construct the circRNA-miRNA-mRNA interactions, and predict circRNA coding potential. A total of 93 differentially expressed circular transcripts were identified in T1D compared with controls, among which 30 were upregulated, and 63 were downregulated. Two circRNAs were identified to have significant differences by RT-PCR. Gene ontology analysis enriched terms such as cellular protein metabolic process, cytoplasm and zinc ion binding. The proposed molecular functions of these differentially expressed circRNAs, including cellular protein metabolic process, cytoplasm, and binding, may contribute to T1D. The most enriched pathways for these circRNAs were involved in protein processing in the endoplasmic reticulum. Hsa_circ_0072697 may be involved in 50 circRNA-miRNA-mRNA signalling pathways related to diabetes, such as circ_0072697-miR-15a-UBASH3A network. Furthermore, hsa_circ_0071224, hsa_circ_0002437, hsa_circ_0084429, hsa_circ_0072697, and hsa_circ_0000787 in T1D were considered to have the most coding potential involved in the pathogenesis of T1D. These results showed that circRNAs are aberrantly expressed in the peripheral blood of patients with T1D and may play potential actions by interactions with miRNA and circRNA-derived peptides in the development of T1D.

Meta‐analysis of differentially expressed microRNAs in systemic sclerosis

Emerging evidence suggests a possible role of microRNAs (miRNAs) that can regulate gene expression in the pathogenesis of systemic sclerosis (SSc). However, contradictory results have been reported on miRNA expression in SSc. We performed a meta-analysis to identify the consistently differentially expressed miRNAs in SSc across studies. We performed a systematic search in PubMed using the terms "microRNAs OR Circulating MicroRNA OR miRNAs" AND "systemic sclerosis OR systemic scleroderma" to identify full-text English publications until 1 August, 2019. After quality assessment using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2), we utilized RevMan 5.3 and Meta-Disc 1.4 to assess heterogeneity (I2 index and Q test P values) and perform effect size modeling. From 120 publications in the initial search, 16 studies on miRNA expression profiles in blood and/or dermal fibroblasts were selected after publication screening. The median number of samples in these studies was 36 (interquartile range 19-59, range 10-119). Meta-analysis revealed 8 differentially expressed miRNAs, of which miR-21 in blood, miR-29a, miR-155, and miR-196a in dermal fibroblasts, and let-7a in both serum and dermal fibroblast samples were most consistent across studies. These miRNAs have been implicated in immune activation, vascular damage, and fibroblast activation, which could potentially lead to the overproduction of collagen and extracellular protein. Studies of miRNA expression in SSc are limited and have used a relatively small number of samples. A meta-analysis of these reports reveals a cluster of differentially expressed miRNAs implicated in immune activation, vascular damage, and fibroblast activation that could play roles in SSc pathogenesis and serve as potential biomarkers.

Manifestly Altered MicroRNAs in Poly Cystic Ovary Syndrome

MicroRNAs (miRNAs) constitute a large family of small non-coding RNAs which regulate gene expression at the surface following transcription. They are widely involved in many physiological and pathological processes including polycystic ovarian syndrome (PCOS). PCOS is an endocrine disorder in women. Currently, there is no comprehensive information about the role of miRNAs in PCOS. Thus, this paper has attempted to collate studies on miRNAs in order to determine important changes in their miRNA expression profile in the total blood, serum, plasma, follicular fluid, and granulosa cells in PCOS patients alongside the genes which are targeted for regulation by these miRNAs. This study presents a new approach for using miRNAs and their target genes for diagnosing and treating PCOS.

Critical Roles of ELVOL4 and IL-33 in the Progression of Obesity-Related Cardiomyopathy via Integrated Bioinformatics Analysis.

The molecular mechanisms underlying obesity-related cardiomyopathy (ORCM) progression involve multiple signaling pathways, and the pharmacological treatment for ORCM is still limited. Thus, it is necessary to explore new targets and develop novel therapies. Microarray analysis for gene expression profiles using different bioinformatics tools has been an effective strategy for identifying novel targets for various diseases. In this study, we aimed to explore the potential genes related to ORCM using the integrated bioinformatics analysis. The GSE18897 (whole blood expression profiling of obese diet-sensitive, obese diet-resistant, and lean human subjects) and GSE47022 (regular weight C57BL/6 and diet-induced obese C57BL/6 mice) were used for bioinformatics analysis. Weighted gene co-expression network analysis (WGCNA) of GSE18897 was employed to investigate gene modules that were strongly correlated with clinical phenotypes. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the co-expression genes. The expression levels of the hub genes were validated in the clinical samples. Yellow co-expression module of WGCNA in GSE18897 was found to be significantly related to the caloric restriction treatment. In addition, GO functional enrichment analysis and KEGG pathway analysis were performed on the co-expression genes in yellow co-expression module, which showed an association with oxygen transport and the porphyrins pathway. Overlap analysis of yellow co-expression module genes from GSE18897 andGSE47022 revealed six upregulated genes, and further experimental validation results showed that elongation of very-long-chain fatty acids protein 4 (ELOVL4), matrix metalloproteinase-8 (MMP-8), and interleukin-33 (IL-33) were upregulated in the peripheral blood from patients with ORCM compared to that in the controls. The bioinformatics analysis revealed that ELOVL4 expression levels are positively correlated with that of IL-33. Collectively, using WGCNA in combination with integrated bioinformatics analysis, the hub genes of ELVOL4 and IL-33 might serve as potential biomarkers for diagnosis and/or therapeutic targets for ORCM. The detailed roles of ELVOL4 and IL-33 in the pathophysiology of ORCM still require further investigation.

Systematic metabolic analysis of potential target, therapeutic drug, diagnostic method and animal model applicability in three neurodegenerative diseases.

Considerable evidence suggests that metabolic abnormalities are associated with neurodegenerative diseases. This study aimed to conduct a systematic metabolic analysis of Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). Human and mouse model microarray datasets were downloaded from the Gene Expression Omnibus database. The metabolic genes and pathways were collected from the Recon 3D human metabolic model. Drug and target information was obtained from the DrugBank database. This study identified ATP1A1, ATP6V1G2, GOT1, HPRT1, MAP2K1, PCMT1 and PLK2 as key metabolic genes that were downregulated in AD, PD and HD. We screened 57 drugs that target these genes, such as digoxin, ouabain and diazoxide. This study constructed multigene diagnostic models for AD, PD and HD by using metabolic gene expression profiles in blood, all models showed high accuracy (AUC > 0.8) both in the experimental and validation sets. Furthermore, analysis of animal models showed that there was almost no consistency among the metabolic changes between mouse models and human diseases. This study systematically revealed the metabolic damage among AD, PD, and HD and uncovered the differences between animal models and human diseases. This information may be helpful for understanding the metabolic mechanisms and drug development for neurodegenerative diseases.

Transcriptome Profiling Reveals Indoxyl Sulfate Should Be Culpable of Impaired T Cell Function in Chronic Kidney Disease

Introduction: Chronic inflammation and immune system dysfunction have been evaluated as major factors in the pathogenesis of chronic kidney disease (CKD), contributing to the high mortality rates observed in these populations. Uremic toxins seem to be the potential “missing link.” Indoxyl sulfate (IS) is one of the protein-bound renal toxins. It participates in multiple pathologies of CKD complications, yet its effect on immune cell has not been studied. This study aimed to explore the genome-wide expression profile in human peripheral blood T cells under stimulation by IS.Methods: In this study, we employed RNA-sequencing transcriptome profiling to identify differentially expressed genes (DEGs) responding to IS stimulation in human peripheral T cells in vitro. Flow cytometry and western blot were used to verify the discovery in RNA-sequencing analysis.Results: Our results yielded a total of 5129 DEGs that were at least twofold up-regulated or down-regulated significantly by IS stimulation and half of them were concentration-specific. Analysis of T cell functional markers revealed a quite different transcription profile under various IS concentration. Transcription factors analysis showed the similar pattern. Aryl hydrocarbon receptor (AhR) target genes CYP1A1, CYP1B1, NQO1, and AhRR were up-regulated by IS stimulation. Pro-inflammatory genes TNF-α and IFN-γ were up-regulated as verified by flow cytometry analysis. DNA damage was induced by IS stimulation as confirmed by elevated protein level of p-ATM, p-ATR, p-BRCA1, and p-p53 in T cells.Conclusion: The toxicity of IS to T cells could be an important source of chronic inflammation in CKD patients. As an endogenous ligand of AhR, IS may influence multiple biological functions of T cells including inflammatory response and cell cycle regulation. Further researches are required to promulgate the underling mechanism and explore effective method of reserving T cell function in CKD.

Differential long non-coding RNA expression profiles in the peripheral blood and CD4+ T cells of patients with active rheumatoid arthritis.

The human transcriptome is primarily composed of long non-coding RNAs (lncRNAs), which are key regulatory molecules of multiple biological processes. In the present study, the expression profiles of lncRNAs in the peripheral blood and CD4+ T cells of patients with active rheumatoid arthritis (RA) were determined. Based on the expression profiles, 493 lncRNAs and 374 mRNAs were identified to be differentially expressed in the peripheral blood of active RA patients and healthy donors. Further verification of lncRNAs was performed using reverse transcription-quantitative (RT-q) PCR analysis of peripheral blood from 5 healthy donors and 5 patients with active RA and 14 additional differentially expressed genes were identified. CD4+ T cells in peripheral blood from 12 patients with active RA and 8 healthy donors were isolated using magnetic beads and qPCR was used to assess differentially expressed lncRNAs. The results suggested that 7 lncRNAs were upregulated and 2 were downregulated. The results indicated that these 9 lncRNAs may be involved in the pathogenesis of RA. An increased ratio of Th17: T-regulatory (Treg) cells was also observed. It may be hypothesized that LncRNAs serve important roles in the differentiation of CD4+ T cells. Receiver operating characteristic curve analysis suggested that these 9 lncRNAs are of potential clinical diagnostic value for RA. Pearson correlation analysis indicated that the correlation coefficient between Ensembl transcript (ENST)00000569543 and complement C4 was 0.623 (P<0.05), and that between ENST00000420096 and anti-cyclic citrullinated peptide antibody or disease activity evaluation score, the correlation coefficient was 0.662 and 0.605, respectively (P<0.05 for each). In conclusion, the results of the present study suggest a possible role of lncRNAs in the differentiation of CD4+ T cells and the pathogenesis of RA, as well as the potential value as diagnostic biomarkers for active RA.

Integrated DNA methylation analysis reveals a potential role for ANKRD30B in Williams syndrome

Williams syndrome (WS) is a rare genetic disorder, caused by a microdeletion at the 7q11.23 region. WS exhibits a wide spectrum of features including hypersociability, which contrasts with social deficits typically associated with autism spectrum disorders. The phenotypic variability in WS likely involves epigenetic modifications; however, the nature of these events remains unclear. To better understand the role of epigenetics in WS phenotypes, we integrated DNA methylation and gene expression profiles in blood from patients with WS and controls. From these studies, 380 differentially methylated positions (DMPs), located throughout the genome, were identified. Systems-level analysis revealed multiple co-methylation modules linked to intermediate phenotypes of WS, with the top-scoring module related to neurogenesis and development of the central nervous system. Notably, ANKRD30B, a promising hub gene, was significantly hypermethylated in blood and downregulated in brain tissue from individuals with WS. Most CpG sites of ANKRD30B in blood were significantly correlated with brain regions. Furthermore, analyses of gene regulatory networks (GRNs) yielded master regulator transcription factors associated with WS. Taken together, this systems-level approach highlights the role of epigenetics in WS, and provides a possible explanation for the complex phenotypes observed in patients with WS.

Transcriptome signatures from discordant sibling pairs reveal changes in peripheral blood immune cell composition in Autism Spectrum Disorder

Notwithstanding several research efforts in the past years, robust and replicable molecular signatures for autism spectrum disorders from peripheral blood remain elusive. The available literature on blood transcriptome in ASD suggests that through accurate experimental design it is possible to extract important information on the disease pathophysiology at the peripheral level. Here we exploit the availability of a resource for molecular biomarkers in ASD, the Italian Autism Network (ITAN) collection, for the investigation of transcriptomic signatures in ASD based on a discordant sibling pair design. Whole blood samples from 75 discordant sibling pairs selected from the ITAN network where submitted to RNASeq analysis and data analyzed by complementary approaches. Overall, differences in gene expression between affected and unaffected siblings were small. In order to assess the contribution of differences in the relative proportion of blood cells between discordant siblings, we have applied two different cell deconvolution algorithms, showing that the observed molecular signatures mainly reflect changes in peripheral blood immune cell composition, in particular NK cells. The results obtained by the cell deconvolution approach are supported by the analysis performed by WGCNA. Our report describes the largest differential gene expression profiling in peripheral blood of ASD subjects and controls conducted by RNASeq. The observed signatures are consistent with the hypothesis of immune alterations in autism and an increased risk of developing autism in subjects exposed to prenatal infections or stress. Our study also points to a potential role of NMUR1, HMGB3, and PTPRN2 in ASD.