scholarly journals Temporal transcriptomic changes in long non-coding RNAs and messenger RNAs involved in the host immune and metabolic response during Toxoplasma gondii lytic cycle

2022 ◽  
Vol 15 (1) ◽  
Author(s):  
Sha-Sha Wang ◽  
Chun-Xue Zhou ◽  
Hany M. Elsheikha ◽  
Jun-Jun He ◽  
Feng-Cai Zou ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Rna Sequencing ◽  
Lytic Cycle ◽  
Differentially Expressed ◽  
Receptor Interaction ◽  
Sequencing Analysis ◽  
Messenger Rnas ◽  
Receptor Signaling ◽  
Non Coding Rnas

Abstract Background Long non-coding RNAs (lncRNAs) are important regulators of various biological and pathological processes, in particular the inflammatory response by modulating the transcriptional control of inflammatory genes. However, the role of lncRNAs in regulating the immune and inflammatory responses during infection with the protozoan parasite Toxoplasma gondii remains largely unknown. Methods We performed a longitudinal RNA sequencing analysis of human foreskin fibroblast (HFF) cells infected by T. gondii to identify differentially expressed long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs), and dysregulated pathways over the course of T. gondii lytic cycle. The transcriptome data were validated by qRT-PCR. Results RNA sequencing revealed significant transcriptional changes in the infected HFFs. A total of 697, 1234, 1499, 873, 1466, 561, 676 and 716 differentially expressed lncRNAs (DElncRNAs), and 636, 1266, 1843, 2303, 3022, 1757, 3088 and 2531 differentially expressed mRNAs (DEmRNAs) were identified at 1.5, 3, 6, 9, 12, 24, 36 and 48 h post-infection, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DElncRNAs and DEmRNAs revealed that T. gondii infection altered the expression of genes involved in the regulation of host immune response (e.g., cytokine–cytokine receptor interaction), receptor signaling (e.g., NOD-like receptor signaling pathway), disease (e.g., Alzheimer's disease), and metabolism (e.g., fatty acid degradation). Conclusions These results provide novel information for further research on the role of lncRNAs in immune regulation of T. gondii infection. Graphical Abstract

RNA sequencing analysis reveals differential gene expression of CXCL2 in ACPA-positive and ACPA-negative rheumatoid arthritis

2020 ◽  
Author(s):  
Lin Sun ◽  
Xinyu Wang ◽  
Ning He ◽  
Zhuo An ◽  
Ruohan Yu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Rna Sequencing ◽  
Differentially Expressed Genes ◽  
Differentially Expressed ◽  
Enzyme Linked Immunosorbent Assay ◽  
Sequencing Analysis ◽  
Healthy Controls ◽  
Raw264.7 Macrophages

Abstract Background. Anti-citrullinated protein/peptide antibodies (ACPA) play important roles in the pathogenesis of rheumatoid arthritis (RA), and are associated with RA severity. It has been suggested that ACPA-positive (ACPA+) and ACPA-negative (ACPA-) RA are different disease subsets with distinct differences in genetic variation and clinical outcomes. The aims of the present study were to compare gene expression profiles in ACPA + and ACPA- RA and identify novel candidate gene signatures that might serve as therapeutic targets. Methods. Comprehensive transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from ACPA + and ACPA- RA patients, and healthy controls was performed via RNA sequencing. Genes with significantly different expressions were analyzed by cluster analysis, Gene Ontology analysis and Ingenuity Pathway analysis. A validation cohort was used to further investigate differentially expressed genes via real-time PCR and enzyme-linked immunosorbent assay. Spearman's correlation test was used to evaluate the correlation of differentially expressed genes and the clinical and laboratory data of the patients. The role of differentially expressed genes in osteoclastogenesis was further investigated. Results. There were significant differences in the expression levels of both genes and gene isoforms between ACPA + and ACPA- RA samples. Expression of C-X-C motif chemokine ligand 2 (CXCL2) was significantly increased in ACPA + RA patients than in ACPA- RA patients and healthy controls. Validation of candidate genes expression showed that CXCL2 levels in PBMCs and serum were higher in ACPA + RA patients than in ACPA- RA patients and healthy controls. CXCL2 promoted the migration of CD14 + monocytes and increased osteoclast differentiation in RA patients. RAW264.7 macrophages were used to investigate specific mechanisms, and the results suggested that CXCL2 stimulated osteoclastogenesis via ERK MAPK and NFκB pathways. Conclusion. Novel pathways associated with ACPA + RA were identified via RNA sequencing, and CXCL2 was highly expressed in ACPA + RA than in ACPA- RA. These results reveal a previously unreported role of CXCL2 during osteoclastogenesis in RA, and suggest that the blockade of CXCL2 might be a novel strategy for the treatment of RA.

Molecular predictors of response to selinexor in advanced unresectable de-differentiated liposarcoma (DDLS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11509-11509
Author(s):  
Christopher James Walker ◽  
Hua Chang ◽  
Jianjun Liu ◽  
Bruno Vincenzi ◽  
Andrea Napolitano ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
B Cell Lymphoma ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Tumor Control ◽  
Double Blind Study ◽  
Sequencing Analysis ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Validation Set

11509 Background: Patients (pts) with recurrent inoperative DDLS have a poor prognosis and limited treatment options. Selinexor is an oral, selective inhibitor of nuclear export (SINE) compound approved for previously treated pts with myeloma and diffuse large B-cell lymphoma. SEAL was a Phase 2-3 randomized, double-blind, study of selinexor versus placebo in pts with progressive DDLS and 2-5 prior systemic therapies. SEAL showed significantly prolonged progression-free survival (PFS, HR = 0.70, p = 0.0228) with well managed toxicity. A biomarker predictive of clinical activity could be used to optimize selection of pts with DDLS for selinexor. Methods: Pts were randomized 2:1 for Phase 3: 188 received twice weekly selinexor (60mg) and 97 received placebo. Three exploratory biomarker analyses (RNA sequencing of biopsies) from selinexor-treated pts were performed: discovery set of sensitive (n = 8) or resistant (n = 9) tumors; a validation set of pts with favorable (n = 19) or poor (n = 14) tumor control based on PFS, and paired lesions from a pt who harbored both a responsive and resistant lesion. Tumor biopsies from 24 pts on placebo with short ( < 5 months, n = 18) and long ( > 6 months, n = 6) PFS were RNA sequenced. Gene expressions were compared using a negative binomial distribution with DeSeq2. Pathway analyses were performed using Gene Set Enrichment Analysis (GSEA) with MSigDB Cancer Gene Neighborhoods. Results: RNA sequencing analysis comparing 17 sensitive and resistant tumors identified 114 differentially expressed genes (adjusted p-values < 0.05). Expression of CALB1, which encodes the calcium-binding protein calbindin, was significantly lower in sensitive tumors (adjusted P [Padj] = 7.5x10-20), and expression of GRM1, which encodes a metabotropic glutamate receptor that activates phospholipase C, was higher in selinexor sensitive tumors (Padj= 0.003). These findings were confirmed in an independent validation set (Padj = 0.01 – 0.02). In the pt with paired sensitive and resistant lesions, CALB1 expression was 52-fold lower in the sensitive tumor. In a comparison of placebo-treated pts, neither CALB1 or GRM1 was differentially expressed between pts with short or long PFS, indicating they are markers of response to selinexor treatment, rather than general markers of disease aggressiveness. Gene set enrichment analyses revealed that selinexor sensitive tumors in the discovery and validation sets showed upregulation of cancer genes related to SNRK and the netrin 1 receptor tumor suppressor DCC. The resistant tumors showed upregulated EIF3S2 translation initiator-related genes. Conclusions: Selinexor sensitive DDLS tumors showed low expression of CALB1 and high GRM1. If validated, pts with DDLS whose tumors match this expression profile are especially likely to benefit from selinexor. Clinical trial information: NCT02606461.

scholarly journals Long Non-coding RNAs RN7SK and GAS5 Regulate Macrophage Polarization and Innate Immune Responses

2020 ◽  
Vol 11 ◽  
Author(s):  
Imran Ahmad ◽  
Araceli Valverde ◽  
Raza Ali Naqvi ◽  
Afsar R. Naqvi
Keyword(s):  
Immune Responses ◽  
Epigenetic Regulation ◽  
Innate Immune ◽  
Differentially Expressed ◽  
Immune Functions ◽  
Innate Immune Responses ◽  
Antigen Uptake ◽  
Non Coding Rnas

Macrophages (Mφ) are immune cells that exhibit remarkable functional plasticity. Identification of novel endogenous factors that can regulate plasticity and innate immune functions of Mφ will unravel new strategies to curb immune-related diseases. Long non-coding RNAs (lncRNAs) are a class of endogenous, non-protein coding, regulatory RNAs that are increasingly being associated with various cellular functions and diseases. Despite their ubiquity and abundance, lncRNA-mediated epigenetic regulation of Mφ polarization and innate immune functions is poorly studied. This study elucidates the regulatory role of lncRNAs in monocyte to Mφ differentiation, M1/M2 dichotomy and innate immune responses. Expression profiling of eighty-eight lncRNAs in monocytes and in vitro differentiated M2 Mφ identified seventeen differentially expressed lncRNAs. Based on fold-change and significance, we selected four differentially expressed lncRNAs viz., RN7SK, GAS5, IPW, and ZFAS1 to evaluate their functional impact. LncRNA knockdown was performed on day 3 M2 Mφ and the impact on polarization was assessed on day 7 by surface marker analysis. Knockdown of RN7SK and GAS5 showed downregulation of M2 surface markers (CD163, CD206, or Dectin) and concomitant increase in M1 markers (MHC II or CD23). RN7SK or GAS5 knockdown showed no significant impact on CD163, CD206, or CD23 transcripts. M1/M2 markers were not impacted by IPW or ZFAS1 knockdown. Functional regulation of antigen uptake/processing and phagocytosis, two central innate immune pathways, by candidate lncRNA was assessed in M1/M2 Mφ. Compared to scramble, enhanced antigen uptake and processing were observed in both M1/M2 Mφ transfected with siRNA targeting GAS5 and RN7SK but not IPW and ZFAS1. In addition, knockdown of RN7SK significantly augmented uptake of labelled E. coli in vitro by M1/M2 Mφ, while no significant difference was in GAS5 silencing cells. Together, our results highlight the instrumental role of lncRNA (RN7SK and GAS5)-mediated epigenetic regulation of macrophage differentiation, polarization, and innate immune functions.

scholarly journals Comprehensive analysis of differentially expressed profiles of long non-coding RNAs and messenger RNAs in kaolin-induced hydrocephalus

Gene ◽  
2019 ◽  
Vol 697 ◽  
pp. 184-193 ◽  
Author(s):  
Yan-Hui Shi ◽  
Xin-Wei He ◽  
Feng-Di Liu ◽  
Yi-Sheng Liu ◽  
Yue Hu ◽  
...  
Keyword(s):  
Comprehensive Analysis ◽  
Differentially Expressed ◽  
Messenger Rnas ◽  
Non Coding Rnas

scholarly journals Identification of Differentially Expressed lncRNAs and mRNAs in Children with Acquired Aplastic Anemia by RNA Sequencing

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Shuanglong Lu ◽  
Xiaoxiao Song ◽  
Jing Chen ◽  
Xiaohong Qiao
Keyword(s):  
Aplastic Anemia ◽  
Rna Sequencing ◽  
Future Study ◽  
Literature Search ◽  
Noncoding Rnas ◽  
Potential Functions ◽  
Differentially Expressed ◽  
Healthy Controls ◽  
Messenger Rnas ◽  
Blood Samples

Background. The effects of long noncoding RNAs (lncRNAs) and their related messenger RNAs (mRNAs) remain unknown in children with acquired aplastic anemia (AA). The aim of this study is to screen key lncRNAs and mRNAs and investigate their potential roles in the pathology of acquired AA in children. Methods. RNA sequencing was performed to identify differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between blood samples of acquired AA children and healthy controls. cis-regulation, trans-regulation, competing endogenous (Ce) regulation networks of DElncRNAs and DEmRNAs were constructed. A literature search was performed to identify immune- or hematopoietic-related DElncRNA-DEmRNA pairs, and qPCR was conducted to validate the expression of the immune- or hematopoietic-related DElncRNA and DEmRNA. Results. 60 DElncRNAs and 364 DEmRNAs were identified. 13 DElncRNAs were predicted to have 15 cis-regulated target DEmRNAs, 16 DElncRNAs might have 28 trans-regulated DEmRNAs, and 2 DElncRNAs might have 9 Ce-regulated DEmRNAs. After literature screen and qPCR validation, 6 immune- or hematopoietic-related DElncRNA-DEmRNA pairs in the networks above were identified as key RNAs in the pathology of acquired AA. Conclusion. This study revealed key lncRNAs in children with acquired AA and proposed their potential functions by predicting their target mRNAs, which lay the foundation for future study of potential effects of lncRNAs in children with acquired AA.

scholarly journals Regulation of Macrophage Activation and Polarization by HCC-Derived Exosomal lncRNA TUC339

2018 ◽  
Vol 19 (10) ◽  
pp. 2958 ◽  
Author(s):  
Xue Li ◽  
Yi Lei ◽  
Miao Wu ◽  
Nan Li
Keyword(s):  
Macrophage Activation ◽  
Cell Function ◽  
Regulatory Function ◽  
Receptor Interaction ◽  
Loss Of Function ◽  
Critical Function ◽  
Over Expression ◽  
Ifn Γ ◽  
Non Coding Rnas

Exosomes released by cells can serve as vehicles for delivery of biological materials and signals. Long non-coding RNAs (lncRNAs) are non-coding RNAs longer than 200 nt, which roles are increasingly appreciated in various biological content. Tumor-derived exosomal lncRNAs have been implicated as signaling mediators to orchestrate cell function among neighbor tumor cells. However, the role of tumor-derived lncRNAs in cross-talk with environmental macrophages has yet to be explored. In this paper, we demonstrated that hepatocellular carcinoma (HCC) cells–derived exosomes contain elevated levels of lncRNA TUC339 and that HCC-derived exosomes could be taken up by THP-1 cells. In seeking to dissect the biological function of tumor secreting TUC339 in macrophages, we applied loss-of-function and gain-of-function strategies. We observed increased pro-inflammatory cytokine production, increased co-stimulatory molecule expression, and enhanced phagocytosis upon suppression of TUC339 by siRNA in THP-1 cells, and the opposite effect upon over-expression of this lncRNA, which indicates that TUC339 was involved in the regulation of macrophage activation. Moreover, we detected an elevated level of TUC339 in M(IL-4) macrophages as compared to M(IFN-γ + LPS) macrophages and a down-regulation of TUC339 expression during M(IL-4)-to-M(IFN-γ + LPS) repolarization and vice versa. Furthermore, suppression of TUC339 in macrophages diminished the expression of M(IL-4) markers upon IL-4 treatment while overexpression of TUC339 in macrophages enhanced M(IL-4) markers upon IFN-γ + LPS treatment, which suggests a critical function of TUC339 in the regulation of macrophage M1/M2 polarization. Lastly, using microarray analysis, we identified cytokine-cytokine receptor interaction, CXCR chemokine receptor binding, Toll-like receptor signaling, FcγR-mediated phagocytosis, regulation of the actin cytoskeleton, and cell proliferation are related with TUC339 function in macrophages. Our results provide evidence for a novel regulatory function of tumor-derived exosomal lncRNA TUC339 in environmental macrophages and shed light on the complicated interactions between tumor and immune cells through exosomal lncRNAs.

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