Sendai virus trailer RNA simultaneously blocks two apoptosis-inducing mechanisms in a cell type-dependent manner

Induction of apoptosis during Sendai virus (SeV) infection has previously been documented to be triggered by initiator caspases (for strain F) or by a contribution of the cellular protein TIAR (T-cell-activated intracellular antigen-related) (for strain Z). Here, evidence was provided that both TIAR and caspases are simultaneously involved in apoptosis induction as a result of infection with SeV strain F. SeV F infection induced death in all tested cell lines, which could only be partially prevented through the pan-caspase inhibitor z-VAD-fmk. However, infection of seven different cell lines with the SeV mutant Fctr48z overexpressing a TIAR-sequestering RNA from the modified leader resulted in a cell type-dependent reduced cytopathic effect (CPE); in an earlier study a similar mutant derived from SeV Z was shown to prevent the induction of any CPE. Finally, blocking of caspases through z-VAD-fmk combined with Fctr48z infection led to complete abrogation of CPE, clearly demonstrating the existence of two separate mechanisms inducing cell death during SeV F infections. Interestingly, a cell type-specific interference between these two mechanisms could be detected during infection with the mutant virus Fctr48z: RNA transcribed from the mutated leader was able to trans-dominantly inhibit caspase-mediated apoptosis. Thus, virus-expressed factors enabling a well-balanced ratio of suppression and triggering of apoptosis seem to be essential for optimal virus replication.

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Either ZEB1 or ZEB2/SIP1 Can Play a Central Role in Regulating the Epstein-Barr Virus Latent-Lytic Switch in a Cell-Type-Specific Manner

Journal of Virology ◽

10.1128/jvi.02706-09 ◽

2010 ◽

Vol 84 (12) ◽

pp. 6139-6152 ◽

Cited By ~ 47

Author(s):

Amy L. Ellis ◽

Zhenxun Wang ◽

Xianming Yu ◽

Janet E. Mertz

Keyword(s):

Cell Lines ◽

Epstein Barr Virus ◽

Cellular Protein ◽

Lytic Replication ◽

Viral Reactivation ◽

Dependent Manner ◽

Cell Type ◽

Barr Virus ◽

A Cell ◽

Epstein Barr

ABSTRACT We previously reported that the cellular protein ZEB1 can repress expression of the Epstein-Barr virus (EBV) BZLF1 gene in transient transfection assays by directly binding its promoter, Zp. We also reported that EBV containing a 2-bp substitution mutation in the ZEB-binding ZV element of Zp spontaneously reactivated out of latency into lytic replication at a higher frequency than did wild-type EBV. Here, using small interfering RNA (siRNA) and short hairpin RNA (shRNA) technologies, we definitively show that ZEB1 is, indeed, a key player in maintaining EBV latency in some epithelial and B-lymphocytic cell lines. However, in other EBV-positive epithelial and B-cell lines, another zinc finger E-box-binding protein, ZEB2/SIP1, is the key player. Both ZEB1 and ZEB2 can bind Zp via the ZV element. In EBV-positive cells containing only ZEB1, knockdown of ZEB1 led to viral reactivation out of latency, with synthesis of EBV immediate-early and early lytic gene products. However, in EBV-positive cells containing both ZEBs, ZEB2, not ZEB1, was the primary ZEB family member bound to Zp. Knockdown of ZEB2, but not ZEB1, led to EBV lytic reactivation. Thus, we conclude that either ZEB1 or ZEB2 can play a central role in the maintenance of EBV latency, doing so in a cell-type-dependent manner.

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Multiple roles of COUP-TFII in cancer initiation and progression

Journal of Molecular Endocrinology ◽

10.1530/jme-12-0144 ◽

2012 ◽

Vol 49 (3) ◽

pp. R135-R148 ◽

Cited By ~ 28

Author(s):

Lacey M Litchfield ◽

Carolyn M Klinge

Keyword(s):

Current Data ◽

Multiple Roles ◽

Dependent Manner ◽

Orphan Nuclear Receptor ◽

Cell Type ◽

Mouse Development ◽

Factor Ii ◽

Upstream Promoter ◽

A Cell ◽

Cell Type Specific

Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is an orphan nuclear receptor that acts as a transcriptional activator or repressor in a cell type-dependent manner. Best characterized for its role in the regulation of angiogenesis during mouse development, COUP-TFII also plays important roles in glucose metabolism and cancer. Expression of COUP-TFII is altered in various endocrine conditions. Cell type-specific functions and the regulation of COUP-TFII expression result in its varying physiological and pathological actions in diverse systems. Evidence will be reviewed for oncogenic and tumor-suppressive functions of COUP-TFII, with roles in angiogenesis, metastasis, steroidogenesis, and endocrine sensitivity of breast cancer described. The applicability of current data to our understanding of the role of COUP-TFII in cancer will be discussed.

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Profiling of Primary and Mature miRNA Expression in Atherosclerosis Associated Cell Types

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.315579 ◽

2021 ◽

Author(s):

Pierre R. Moreau ◽

Vanesa Tomas Bosch ◽

Maria Bouvy-Liivrand ◽

Kadri Õunap ◽

Tiit Örd ◽

...

Keyword(s):

Endothelial Cells ◽

Smooth Muscle ◽

Molecular Mechanisms ◽

Umbilical Vein ◽

Cell Types ◽

Integrative Approach ◽

Dependent Manner ◽

Cell Type ◽

A Cell ◽

Cell Type Specific

Objective: Atherosclerosis is the underlying cause of most cardiovascular diseases. The main cell types associated with disease progression in the vascular wall are endothelial cells, smooth muscle cells, and macrophages. Although their role in atherogenesis has been extensively described, molecular mechanisms underlying gene expression changes remain unknown. The objective of this study was to characterize microRNA (miRNA)-related regulatory mechanisms taking place in the aorta during atherosclerosis: Approach and Results: We analyzed the changes in primary human aortic endothelial cells and human umbilical vein endothelial cell, human aortic smooth muscle cell, and macrophages (CD14+) under various proatherogenic stimuli by integrating GRO-seq, miRNA-seq, and RNA-seq data. Despite the highly cell-type-specific expression of multi-variant pri-miRNAs, the majority of mature miRNAs were found to be common to all cell types and dominated by 2 to 5 abundant miRNA species. We demonstrate that transcription contributes significantly to the mature miRNA levels although this is dependent on miRNA stability. An analysis of miRNA effects in relation to target mRNA pools highlighted pathways and targets through which miRNAs could affect atherogenesis in a cell-type-dependent manner. Finally, we validate miR-100-5p as a cell-type specific regulator of inflammatory and HIPPO-YAP/TAZ-pathways. Conclusions: This integrative approach allowed us to characterize miRNA dynamics in response to a proatherogenic stimulus and identify potential mechanisms by which miRNAs affect atherogenesis in a cell-type-specific manner.

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CD300LF Polymorphisms of Inbred Mouse Strains Confer Resistance to Murine Norovirus Infection in a Cell Type-Dependent Manner

Journal of Virology ◽

10.1128/jvi.00837-20 ◽

2020 ◽

Vol 94 (17) ◽

Author(s):

Kevin Furlong ◽

Scott B. Biering ◽

Jayoung Choi ◽

Craig B. Wilen ◽

Robert C. Orchard ◽

...

Keyword(s):

Cell Types ◽

Host Cells ◽

Mouse Strains ◽

Specific Cell ◽

Dependent Manner ◽

Murine Norovirus ◽

Cell Type ◽

Human Norovirus ◽

A Cell ◽

Cell Type Specific

ABSTRACT Human norovirus is the leading cause of gastroenteritis worldwide, yet basic questions about its life cycle remain unanswered due to an historical lack of robust experimental systems. Recent studies on the closely related murine norovirus (MNV) have identified CD300LF as an indispensable entry factor for MNV. We compared the MNV susceptibilities of cells from different mouse strains and identified polymorphisms in murine CD300LF which are critical for its function as an MNV receptor. Bone marrow-derived macrophages (BMDMs) from I/LnJ mice were resistant to infection from multiple MNV strains which readily infect BMDMs from C57BL/6J mice. The resistance of I/LnJ BMDMs was specific to MNV, since the cells supported infection of other viruses comparably to C57BL/6J BMDMs. Transduction of I/LnJ BMDMs with C57BL/6J CD300LF made the cells permissible to MNV infection, suggesting that the cause of resistance lies in the entry step of MNV infection. In fact, we mapped this phenotype to a 4-amino-acid difference at the CC′ loop of CD300LF; swapping of these amino acids between C57BL/6J and I/LnJ CD300LF proteins made the mutant C57BL/6J CD300LF functionally impaired and the corresponding mutant of I/LnJ CD300LF functional as an MNV entry factor. Surprisingly, expression of the I/LnJ CD300LF in other cell types made the cells infectible by MNV, even though the I/LnJ allele did not function as an MNV receptor in macrophage-like cells. Correspondingly, I/LnJ CD300LF bound MNV virions in permissive cells but not in nonpermissive cells. Collectively, our data suggest the existence of a cell type-specific modifier of MNV entry. IMPORTANCE MNV is a prevalent model system for studying human norovirus, which is the leading cause of gastroenteritis worldwide and thus a sizeable public health burden. Elucidating mechanisms underlying susceptibility of host cells to MNV infection can lead to insights on the roles that specific cell types play during norovirus pathogenesis. Here, we show that different alleles of the proteinaceous receptor for MNV, CD300LF, function in a cell type-dependent manner. In contrast to the C57BL/6J allele, which functions as an MNV entry factor in all tested cell types, including human cells, I/LnJ CD300LF does not function as an MNV entry factor in macrophage-like cells but does allow MNV entry in other cell types. Together, these observations indicate the existence of cell type-specific modifiers of CD300LF-dependent MNV entry.

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Long Non-Coding RNA Expression Levels Modulate Cell-Type-Specific Splicing Patterns by Altering Their Interaction Landscape with RNA-Binding Proteins

Genes ◽

10.3390/genes10080593 ◽

2019 ◽

Vol 10 (8) ◽

pp. 593 ◽

Cited By ~ 4

Author(s):

Felipe Wendt Porto ◽

Swapna Vidhur Daulatabad ◽

Sarath Chandra Janga

Keyword(s):

Alternative Splicing ◽

Cell Lines ◽

Rna Binding ◽

Cell Type ◽

Specific Manner ◽

Alternatively Spliced ◽

A Cell ◽

Specific Alternative ◽

Cell Type Specific ◽

Rna Interaction

Recent developments in our understanding of the interactions between long non-coding RNAs (lncRNAs) and cellular components have improved treatment approaches for various human diseases including cancer, vascular diseases, and neurological diseases. Although investigation of specific lncRNAs revealed their role in the metabolism of cellular RNA, our understanding of their contribution to post-transcriptional regulation is relatively limited. In this study, we explore the role of lncRNAs in modulating alternative splicing and their impact on downstream protein–RNA interaction networks. Analysis of alternative splicing events across 39 lncRNA knockdown and wildtype RNA-sequencing datasets from three human cell lines—HeLa (cervical cancer), K562 (myeloid leukemia), and U87 (glioblastoma)—resulted in the high-confidence (false discovery rate (fdr) < 0.01) identification of 11,630 skipped exon events and 5895 retained intron events, implicating 759 genes to be impacted at the post-transcriptional level due to the loss of lncRNAs. We observed that a majority of the alternatively spliced genes in a lncRNA knockdown were specific to the cell type. In tandem, the functions annotated to the genes affected by alternative splicing across each lncRNA knockdown also displayed cell-type specificity. To understand the mechanism behind this cell-type-specific alternative splicing pattern, we analyzed RNA-binding protein (RBP)–RNA interaction profiles across the spliced regions in order to observe cell-type-specific alternative splice event RBP binding preference. Despite limited RBP binding data across cell lines, alternatively spliced events detected in lncRNA perturbation experiments were associated with RBPs binding in proximal intron–exon junctions in a cell-type-specific manner. The cellular functions affected by alternative splicing were also affected in a cell-type-specific manner. Based on the RBP binding profiles in HeLa and K562 cells, we hypothesize that several lncRNAs are likely to exhibit a sponge effect in disease contexts, resulting in the functional disruption of RBPs and their downstream functions. We propose that such lncRNA sponges can extensively rewire post-transcriptional gene regulatory networks by altering the protein–RNA interaction landscape in a cell-type-specific manner.

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Glucocorticoids suppress macrophage migration inhibitory factor (MIF) expression in a cell-type-specific manner

Journal of Molecular Endocrinology ◽

10.1677/jme.1.01647 ◽

2005 ◽

Vol 34 (2) ◽

pp. 583-595 ◽

Cited By ~ 19

Author(s):

Z Alourfi ◽

R P Donn ◽

A Stevens ◽

A Berry ◽

A McMaster ◽

...

Keyword(s):

Inflammatory Diseases ◽

A549 Cells ◽

Lung Epithelial Cells ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Dependent Manner ◽

Cell Type ◽

A Cell ◽

Cell Type Specific ◽

T Lymphoblasts

MIF is a potent proinflammatory cytokine involved in inflammatory arthritis. Glucocorticoids (GC) have been reported to induce secretion of MIF in rodent cells, and as MIF counteracts the anti-inflammatory effects of GC, this has implications for human inflammatory disease. Transient transfection studies showed that the MIF promoter was repressed by dexamethasone (Dex) (10 nM) in CEM C7A cells, with up to 50% suppression by 100 nM. However, there was no regulation of the promoter by GC in A549 cells. We also found that subnanomolar concentrations of Dex suppressed MIF secretion, measured by ELISA, by 80% in both human T lymphoblasts (CEM C7A) and human lung epithelial cells (A549). Endogenous MIF mRNA was also repressed by GC in CEM C7A cells, measured both by Northern blot and quantitative RT-PCR assays, but there was no such regulation in A549 cells. This suggests that GC affects translation rather than transcription of MIF in A549 cells. These results contradict earlier results with the rat cell line RAW 264.7. Therefore, we analysed MIF secretion from RAW 264.7 cells but found no GC effect on secretion. Understanding how GC regulates MIF in a cell-type-dependent manner may give insights into GC-refractory human inflammatory diseases.

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Activation of Innate Defense against a Paramyxovirus Is Mediated by RIG-I and TLR7 and TLR8 in a Cell-Type-Specific Manner

Journal of Virology ◽

10.1128/jvi.79.20.12944-12951.2005 ◽

2005 ◽

Vol 79 (20) ◽

pp. 12944-12951 ◽

Cited By ~ 126

Author(s):

Jesper Melchjorsen ◽

Søren B. Jensen ◽

Lene Malmgaard ◽

Simon B. Rasmussen ◽

Friedemann Weber ◽

...

Keyword(s):

Sendai Virus ◽

Large Degree ◽

Molecular Structures ◽

Dependent Manner ◽

Cell Type ◽

Cell Type Specificity ◽

Protein Kinase R ◽

Innate Defense ◽

Expression Of Genes ◽

A Cell

ABSTRACT Recognition of pathogens by the innate immune system is mediated by pattern recognition receptors (PRRs), which recognize specific molecular structures of the infectious agents and subsequently trigger expression of genes involved in host defense. Toll-like receptors (TLRs) represent a well-characterized class of membrane-bound PRRs, and the RNA helicase retinoic acid inducible gene I (RIG-I) has recently been described as a novel cytoplasmic PRR recognizing double-stranded RNA (dsRNA). Here we show that activation of signal transduction and induction of cytokine expression by the paramyxovirus Sendai virus is dependent on virus replication and involves PRRs in a cell-type-dependent manner. While nonimmune cells relied entirely on recognition of dsRNA through RIG-I for activation of an antiviral response, myeloid cells utilized both the single-stranded RNA sensing TLR7 and TLR8 and dsRNA-dependent mechanisms independent of RIG-I, TLR3, and dsRNA-activated protein kinase R to trigger this response. Therefore, there appears to be a large degree of cell-type specificity in the mechanisms used by the host to recognize infecting viruses.

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Protopine/Gemcitabine Combination Induces Cytotoxic or Cytoprotective Effects in Cell Type-Specific and Dose-Dependent Manner on Human Cancer and Normal Cells

Pharmaceuticals ◽

10.3390/ph14020090 ◽

2021 ◽

Vol 14 (2) ◽

pp. 90

Author(s):

Mercedes Garcia-Gil ◽

Benedetta Turri ◽

Morena Gabriele ◽

Laura Pucci ◽

Alessandro Agnarelli ◽

...

Keyword(s):

Cell Lines ◽

Human Cancer ◽

Human Tumor ◽

Dermal Fibroblasts ◽

Dependent Manner ◽

Cell Type ◽

Mitochondrial Ros ◽

Cell Type Specific ◽

Natural Alkaloid ◽

Dose Dependent

The natural alkaloid protopine (PRO) exhibits pharmacological properties including anticancer activity. We investigated the effects of PRO, alone and in combination with the chemotherapeutic gemcitabine (GEM), on human tumor cell lines and non-tumor human dermal fibroblasts (HDFs). We found that treatments with different PRO/GEM combinations were cytotoxic or cytoprotective, depending on concentration and cell type. PRO/GEM decreased viability in pancreatic cancer MIA PaCa-2 and PANC-1 cells, while it rescued the GEM-induced viability decline in HDFs and in tumor MCF-7 cells. Moreover, PRO/GEM decreased G1, S and G2/M phases, concomitantly with an increase of subG1 phase in MIA PaCa-2 and PANC-1 cells. Differently, PRO/GEM restored the normal progression of the cell cycle, altered by GEM, and decreased cell death in HDFs. PRO alone increased mitochondrial reactive oxygen species (ROS) in MIA PaCa-2, PANC-1 cells and HDFs, while PRO/GEM increased both intracellular and mitochondrial ROS in the three cell lines. These results indicate that specific combinations of PRO/GEM may be used to induce cytotoxic effects in pancreatic tumor MIA PaCa-2 and PANC-1 cells, but have cytoprotective or no effects in HDFs.

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Genistein Enhances or Reduces Glycosaminoglycan Quantity in a Cell Type-Specific Manner

Cellular Physiology and Biochemistry ◽

10.1159/000490985 ◽

2018 ◽

Vol 47 (4) ◽

pp. 1667-1681

Author(s):

Ying Lan ◽

Xiulian Li ◽

Xuebo Liu ◽

Cui Hao ◽

Ni Song ◽

...

Keyword(s):

Molecular Mechanisms ◽

Isotope Labeling ◽

Dependent Manner ◽

Cell Type ◽

Beneficial Effects ◽

Genistein Treatment ◽

Specific Manner ◽

A Cell ◽

Cell Type Specific ◽

Hct116 Cells

Background/Aims: Genistein is a natural isoflavone enriched in soybeans. It has beneficial effects for patients with mucopolysaccharidose type III through inhibiting glycosaminoglycan biosynthesis. However, other studies indicate that genistein does not always inhibit glycosaminoglycan biosynthesis. Methods: To understand the underlying molecular mechanisms, CHOK1, CHO3.1, CHO3.3, and HCT116 cells were treated with genistein and the monosaccharide compositions and quantity of all glycans from the cell lysate were measured after thorough acid hydrolysis followed by HPLC analysis. In addition, the glycosaminoglycan disaccharide compositions were obtained by stable isotope labeling coupled with LC/MS analysis. Results: Genistein treatment reduced the amount of glycans but increased the amount of glycosaminoglycans in HCT116 cells. In contrast, genistein treatment reduced both glycan and glycosaminoglycan quantities in CHOK1, CHO3.1, and CHO3.3 cells in addition to differential changes in glycosaminoglycan disaccharide compositions. Conclusion: Genistein treatment reduced overall glycan quantity but glycosaminoglycan quantities were either increased or decreased in a cell type-dependent manner.

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Predicting cell-type-specific non-coding RNA transcription from genome sequence

10.1101/2020.03.29.011205 ◽

2020 ◽

Author(s):

Masaru Koido ◽

Chung-Chau Hon ◽

Satoshi Koyama ◽

Hideya Kawaji ◽

Yasuhiro Murakawa ◽

...

Keyword(s):

Complex Traits ◽

Complex Trait ◽

Cell Types ◽

Dependent Manner ◽

Genetic Associations ◽

Cell Type ◽

Non Coding Rna ◽

Causal Variants ◽

A Cell ◽

Cell Type Specific

SUMMARYTranscription is regulated through complex mechanisms involving non-coding RNAs (ncRNAs). However, because transcription of ncRNAs, especially enhancer RNAs, is often low and cell type-specific, its dependency on genotype remains largely unexplored. Here, we developed mutation effect prediction on ncRNA transcription (MENTR), a quantitative machine learning framework reliably connecting genetic associations with expression of ncRNAs, resolved to the level of cell type. MENTR-predicted mutation effects on ncRNA transcription were concordant with estimates from previous genetic studies in a cell type-dependent manner. We inferred reliable causal variants from 41,223 GWAS variants, and proposed 7,775 enhancers and 3,548 long-ncRNAs as complex trait-associated ncRNAs in 348 major human primary cells and tissues, including plausible enhancer-mediated functional alterations in single-variant resolution in Crohn’s disease. In summary, we present new resources for discovering causal variants, the biological mechanisms driving complex traits, and the sequence-dependency of ncRNA regulation in relevant cell types.

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