R-loops coordinate with SOX2 in regulating reprogramming to pluripotency

R-loops modulate genome stability and regulate gene expression, but the functions and the regulatory mechanisms of R-loops in stem cell biology are still unclear. Here, we profiled R-loops during somatic cell reprogramming and found that dynamic changes in R-loops are essential for reprogramming and occurred before changes in gene expression. Disrupting the homeostasis of R-loops by depleting RNaseH1 or catalytic inactivation of RNaseH1 at D209 (RNaseH1D209N) blocks reprogramming. Sox2, but not any other factor in the Yamanaka cocktail, overcomes the inhibitory effects of RNaseH1 activity loss on reprogramming. Sox2 interacts with the reprogramming barrier factor Ddx5 and inhibits the resolvase activity of Ddx5 on R-loops and thus facilitates reprogramming. Furthermore, reprogramming efficiency can be modulated by dCas9-mediated RNaseH1/RNaseH1D209N targeting the specific R-loop regions. Together, these results show that R-loops play important roles in reprogramming and shed light on the regulatory module of Sox2/Ddx5 on R-loops during reprogramming.

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Cytoskeletal proteins in the cell nucleus: a special nuclear actin perspective

Molecular Biology of the Cell ◽

10.1091/mbc.e18-10-0645 ◽

2019 ◽

Vol 30 (15) ◽

pp. 1781-1785 ◽

Cited By ~ 16

Author(s):

Piergiorgio Percipalle ◽

Maria Vartiainen

Keyword(s):

Gene Expression ◽

Cell Nucleus ◽

Cell Biology ◽

Genome Stability ◽

Actin Polymerization ◽

Nuclear Architecture ◽

Nuclear Lamina ◽

Cytoskeletal Proteins ◽

Actin Binding ◽

Special Focus

The emerging role of cytoskeletal proteins in the cell nucleus has become a new frontier in cell biology. Actin and actin-binding proteins regulate chromatin and gene expression, but importantly they are beginning to be essential players in genome organization. These actin-based functions contribute to genome stability and integrity while affecting DNA replication and global transcription patterns. This is likely to occur through interactions of actin with nuclear components including nuclear lamina and subnuclear organelles. An exciting future challenge is to understand how these actin-based genome-wide mechanisms may regulate development and differentiation by interfering with the mechanical properties of the cell nucleus and how regulated actin polymerization plays a role in maintaining nuclear architecture. With a special focus on actin, here we summarize how cytoskeletal proteins operate in the nucleus and how they may be important to consolidate nuclear architecture for sustained gene expression or silencing.

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Switching of vascular cells towards atherogenesis, and other factors contributing to atherosclerosis: a systematic review

Thrombosis Journal ◽

10.1186/s12959-020-00240-z ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Ovais Shafi

Keyword(s):

Gene Expression ◽

Signaling Pathways ◽

Cell Biology ◽

Genome Stability ◽

Cell Types ◽

Vascular Cells ◽

Vascular Cell ◽

Vascular Homeostasis ◽

Apoptotic Pathways ◽

Progression Of Atherosclerosis

Abstract Background Onset, development and progression of atherosclerosis are complex multistep processes. Many aspects of atherogenesis are not yet properly known. This study investigates the changes in vasculature that contribute to switching of vascular cells towards atherogenesis, focusing mainly on ageing. Methods Databases including PubMed, MEDLINE and Google Scholar were searched for published articles without any date restrictions, involving atherogenesis, vascular homeostasis, aging, gene expression, signaling pathways, angiogenesis, vascular development, vascular cell differentiation and maintenance, vascular stem cells, endothelial and vascular smooth muscle cells. Results Atherogenesis is a complex multistep process that unfolds in a sequence. It is caused by alterations in: epigenetics and genetics, signaling pathways, cell circuitry, genome stability, heterotypic interactions between multiple cell types and pathologic alterations in vascular microenvironment. Such alterations involve pathological changes in: Shh, Wnt, NOTCH signaling pathways, TGF beta, VEGF, FGF, IGF 1, HGF, AKT/PI3K/ mTOR pathways, EGF, FOXO, CREB, PTEN, several apoptotic pathways, ET – 1, NF-κB, TNF alpha, angiopoietin, EGFR, Bcl − 2, NGF, BDNF, neurotrophins, growth factors, several signaling proteins, MAPK, IFN, TFs, NOs, serum cholesterol, LDL, ephrin, its receptor pathway, HoxA5, Klf3, Klf4, BMPs, TGFs and others. This disruption in vascular homeostasis at cellular, genetic and epigenetic level is involved in switching of the vascular cells towards atherogenesis. All these factors working in pathologic manner, contribute to the development and progression of atherosclerosis. Conclusion The development of atherosclerosis involves the switching of gene expression towards pro-atherogenic genes. This happens because of pathologic alterations in vascular homeostasis. When pathologic alterations in epigenetics, genetics, regulatory genes, microenvironment and vascular cell biology accumulate beyond a specific threshold, then the disease begins to express itself phenotypically. The process of biological ageing is one of the most significant factors in this aspect as it is also involved in the decline in homeostasis, maintenance and integrity. The process of atherogenesis unfolds sequentially (step by step) in an interconnected loop of pathologic changes in vascular biology. Such changes are involved in ‘switching’ of vascular cells towards atherosclerosis.

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Time-resolved transcriptional profiling of Trichinella-infected murine myocytes helps to elucidate host–pathogen interactions in the muscle stage

Parasites & Vectors ◽

10.1186/s13071-021-04624-6 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Xiaoxiang Hu ◽

Xiaolei Liu ◽

Chen Li ◽

Yulu Zhang ◽

Chengyao Li ◽

...

Keyword(s):

Gene Expression ◽

Cell Biology ◽

Trichinella Spiralis ◽

Expression Patterns ◽

Muscle Cells ◽

Host Cells ◽

Initial Reaction ◽

Global Changes ◽

Mammalian Skeletal Muscle ◽

Time Resolved

Abstract Background Parasites of the genus Trichinella are the pathogenic agents of trichinellosis, which is a widespread and severe foodborne parasitic disease. Trichinella spiralis resides primarily in mammalian skeletal muscle cells. After invading the cells of the host organism, T. spiralis must elude or invalidate the host’s innate and adaptive immune responses to survive. It is necessary to characterize the pathogenesis of trichinellosis to help to prevent the occurrence and further progression of this disease. The aims of this study were to elucidate the mechanisms of nurse cell formation, pathogenesis and immune evasion of T. spiralis, to provide valuable information for further research investigating the basic cell biology of Trichinella-infected muscle cells and the interaction between T. spiralis and its host. Methods We performed transcriptome profiling by RNA sequencing to identify global changes at 1, 3, 7, 10 and 15 days post-infection (dpi) in gene expression in the diaphragm after the parasite entered and persisted within the murine myocytes; the mice were infected by intravenous injection of newborn larvae. Gene expression analysis was based on the alignment results. Differentially expressed genes (DEGs) were identified based on their expression levels in various samples, and functional annotation and enrichment analysis were performed. Results The most extensive and dynamic gene expression responses in host diaphragms were observed during early infection (1 dpi). The number of DEGs and genes annotated in the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology databases decreased significantly in the infected mice compared to the uninfected mice at 3 and 7 dpi, suddenly increased sharply at 10 dpi, and then decreased to a lower level at 15 dpi, similar to that observed at 3 and 7 dpi. The massive initial reaction of the murine muscle cells to Trichinella infection steadied in the later stages of infection, with little additional changes detected for the remaining duration of the studied process. Although there were hundreds of DEGs at each time point, only 11 genes were consistently up- or downregulated at all 5 time points. Conclusions The gene expression patterns identified in this study can be employed to characterize the coordinated response of T. spiralis-infected myocytes in a time-resolved manner. This comprehensive dataset presents a distinct and sensitive picture of the interaction between host and parasite during intracellular infection, which can help to elucidate how pathogens evade host defenses and coordinate the biological functions of host cells to survive in the mammalian environment.

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Expression of DDX11 and DNM1L at the 12p11 Locus Modulates Systemic Lupus Erythematosus Susceptibility

International Journal of Molecular Sciences ◽

10.3390/ijms22147624 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7624

Author(s):

Mohammad Saeed ◽

Alejandro Ibáñez-Costa ◽

Alejandra María Patiño-Trives ◽

Laura Muñoz-Barrera ◽

Eduardo Collantes Estévez ◽

...

Keyword(s):

Gene Expression ◽

Lupus Erythematosus ◽

Genome Stability ◽

Meta Analysis ◽

Susceptibility Gene ◽

Significant Snps ◽

Differentially Expressed ◽

Systemic Lupus Erythematosus Susceptibility ◽

Functional Pathways ◽

Functional Analyses

Objectives: This study employed genetic and functional analyses using OASIS meta-analysis of multiple existing GWAS and gene-expression datasets to identify novel SLE genes. Methods: Four hundred and ten genes were mapped using SNIPPER to 30 SLE GWAS loci and investigated for expression in three SLE GEO-datasets and the Cordoba GSE50395-dataset. Blood eQTL for significant SNPs in SLE loci and STRING for functional pathways of differentially expressed genes were used. Confirmatory qPCR on SLE monocytes was performed. The entire 12p11 locus was investigated for genetic association using two additional GWAS. Expression of 150 genes at this locus was assessed. Based on this significance, qPCRs for DNM1L and KRAS were performed. Results: Fifty genes were differentially expressed in at least two SLE GEO-datasets, with all probes directionally aligned. DDX11, an RNA helicase involved in genome stability, was downregulated in both GEO and Cordoba datasets. The most significant SNP, rs3741869 in OASIS locus 12p11.21, containing DDX11, was a cis-eQTL regulating DDX11 expression. DDX11 was found repressed. The entire 12p11 locus showed three association peaks. Gene expression in GEO datasets identified DNM1L and KRAS, besides DDX11. Confirmatory qPCR validated DNM1L as an SLE susceptibility gene. DDX11, DNM1L and KRAS interact with each other and multiple known SLE genes including STAT1/STAT4 and major components of IFN-dependent gene expression, and are responsible for signal transduction of cytokines, hormones, and growth-factors, deregulation of which is involved in SLE-development. Conclusion: A genomic convergence approach with OASIS analysis of multiple GWAS and expression datasets identified DDX11 and DNM1L as novel SLE-genes, the expression of which is altered in monocytes from SLE patients. This study lays the foundation for understanding the pathogenic involvement of DDX11 and DNM1L in SLE by identifying them using a systems-biology approach, while the 12p11 locus harboring these genes was previously missed by four independent GWAS.

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The Stress Response: Changes in Eukaryotic Gene Expression in Response to Environmental Stress . Burr G. Atkinson and David B. Walden, Eds. Academic Press, Orlando, Fla., 1985. xviii, 381 pp., illus. $65. Cell Biology.

Science ◽

10.1126/science.230.4727.800.b ◽

1985 ◽

Vol 230 (4727) ◽

pp. 800-801

Author(s):

Elizabeth A. Craig

Keyword(s):

Gene Expression ◽

Stress Response ◽

Environmental Stress ◽

Cell Biology ◽

Academic Press ◽

Eukaryotic Gene Expression ◽

Eukaryotic Gene

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Maize Small RNAs as Seeds of Change and Stability in Gene Expression and Genome Stability

Compendium of Plant Genomes - The Maize Genome ◽

10.1007/978-3-319-97427-9_8 ◽

2018 ◽

pp. 113-127

Author(s):

Reza Hammond ◽

Chong Teng ◽

Blake C. Meyers

Keyword(s):

Gene Expression ◽

Small Rnas ◽

Genome Stability

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Identification of endothelial cell genes by combined database mining and microarray analysis

Physiological Genomics ◽

10.1152/physiolgenomics.00186.2002 ◽

2003 ◽

Vol 13 (3) ◽

pp. 249-262 ◽

Cited By ~ 80

Author(s):

Michael Ho ◽

Eugene Yang ◽

George Matcuk ◽

David Deng ◽

Nick Sampas ◽

...

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Endothelial Cell ◽

Cell Biology ◽

Soft Tissues ◽

Expression Profiles ◽

Differentially Expressed ◽

Primary Data ◽

Database Mining ◽

Novel Genes

Vascular endothelial cells maintain the interface between the systemic circulation and soft tissues and mediate critical processes such as inflammation in a vascular bed-selective fashion. To expand our understanding of the genetic pathways that underlie these specific functions, we have focused on the identification of novel genes that are differentially expressed in all endothelial cells, as well as restricted groups of this cell type. Virtual subtraction was conducted employing gene expression data deposited in public databases and 384 genes identified.11 The microarray data derived through these experiments have been deposited in the GEO expression database at the NCBI and has been given the accession number GPL217 , with others pending. Primary data and supplementary material associated with this manuscript are being deposited at the following website: http://quertermous.stanford.edu . These genes were spotted on custom microarrays, along with 288 genes identified through subtraction cloning from TGF-β-stimulated endothelial cells. Arrays were evaluated with RNA samples representing endothelial cells cultured from four vascular sources and five non-endothelial cell types. These studies identified 64 pan-endothelial markers that were differentially expressed with at least a threefold difference (range 3- to 55-fold). In addition, differences in gene expression profiles among endothelial cells from different vascular beds were identified. Validation of these findings was performed by RNA blot expression studies, and a number of the novel genes were shown to be expressed under angiogenic conditions in the developing mouse embryo. The combined tools of database mining and transcriptional profiling thus provide expanded knowledge of endothelial cell gene expression and endothelial cell biology.

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Fibronectin isoform gene expression in rat hepatic stellate and parenchymal cells of normal and fibrotic liver . Laboratory for Cell Biology and Histology, (1) Laboratory for Toxicology, Free University Brussels (V.U.B.), and (2) Department of Anatomy, University of Helsinki

Hepatology ◽

10.1016/0270-9139(95)95196-2 ◽

1995 ◽

Vol 22 (4) ◽

pp. A369

Keyword(s):

Gene Expression ◽

Cell Biology ◽

Fibrotic Liver ◽

Parenchymal Cells

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A novel member of the SAF (scaffold attachment factor)-box protein family inhibits gene expression and induces apoptosis

Biochemical Journal ◽

10.1042/bj20070170 ◽

2007 ◽

Vol 407 (3) ◽

pp. 355-362 ◽

Cited By ~ 21

Author(s):

Ching Wan Chan ◽

Youn-Bok Lee ◽

James Uney ◽

Andrea Flynn ◽

Jonathan H. Tobias ◽

...

Keyword(s):

Gene Expression ◽

Rna Binding ◽

Chromatin Condensation ◽

Inhibitory Effect ◽

Binding Motif ◽

Inhibitory Effects ◽

Cytochrome C Release ◽

Interacting Protein ◽

Induced Apoptosis ◽

Attachment Factor

The SLTM [SAF (scaffold attachment factor)-like transcription modulator] protein contains a SAF-box DNA-binding motif and an RNA-binding domain, and shares an overall identity of 34% with SAFB1 {scaffold attachment factor-B1; also known as SAF-B (scaffold attachment factor B), HET [heat-shock protein 27 ERE (oestrogen response element) and TATA-box-binding protein] or HAP (heterogeneous nuclear ribonucleoprotein A1-interacting protein)}. Here, we show that SLTM is localized to the cell nucleus, but excluded from nucleoli, and to a large extent it co-localizes with SAFB1. In the nucleus, SLTM has a punctate distribution and it does not co-localize with SR (serine/arginine) proteins. Overexpression of SAFB1 has been shown to exert a number of inhibitory effects, including suppression of oestrogen signalling. Although SLTM also suppressed the ability of oestrogen to activate a reporter gene in MCF-7 breast-cancer cells, inhibition of a constitutively active β-galactosidase gene suggested that this was primarily the consequence of a generalized inhibitory effect on transcription. Measurement of RNA synthesis, which showed a particularly marked inhibition of [3H]uridine incorporation into mRNA, supported this conclusion. In addition, analysis of cell-cycle parameters, chromatin condensation and cytochrome c release showed that SLTM induced apoptosis in a range of cultured cell lines. Thus the inhibitory effects of SLTM on gene expression appear to result from generalized down-regulation of mRNA synthesis and initiation of apoptosis consequent upon overexpressing the protein. While indicating a crucial role for SLTM in cellular function, these results also emphasize the need for caution when interpreting phenotypic changes associated with manipulation of protein expression levels.

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