scholarly journals DIANA-miRGen v4: indexing promoters and regulators for more than 1500 microRNAs

2020 ◽  
Vol 49 (D1) ◽  
pp. D151-D159
Author(s):  
Nikos Perdikopanis ◽  
Georgios K Georgakilas ◽  
Dimitris Grigoriadis ◽  
Vasilis Pierros ◽  
Ioannis Kavakiotis ◽  
...  
Keyword(s):  
Critical Role ◽  
Cell Types ◽  
Mirna Biogenesis ◽  
Transcriptional Level ◽  
Pathological State ◽  
Transcription Start Sites ◽  
Multiple Cell ◽  
Underlying Mechanisms ◽  
Cap Analysis ◽  
User Friendly

Abstract Deregulation of microRNA (miRNA) expression plays a critical role in the transition from a physiological to a pathological state. The accurate miRNA promoter identification in multiple cell types is a fundamental endeavor towards understanding and characterizing the underlying mechanisms of both physiological as well as pathological conditions. DIANA-miRGen v4 (www.microrna.gr/mirgenv4) provides cell type specific miRNA transcription start sites (TSSs) for over 1500 miRNAs retrieved from the analysis of >1000 cap analysis of gene expression (CAGE) samples corresponding to 133 tissues, cell lines and primary cells available in FANTOM repository. MiRNA TSS locations were associated with transcription factor binding site (TFBSs) annotation, for >280 TFs, derived from analyzing the majority of ENCODE ChIP-Seq datasets. For the first time, clusters of cell types having common miRNA TSSs are characterized and provided through a user friendly interface with multiple layers of customization. DIANA-miRGen v4 significantly improves our understanding of miRNA biogenesis regulation at the transcriptional level by providing a unique integration of high-quality annotations for hundreds of cell specific miRNA promoters with experimentally derived TFBSs.

Na-K-Cl cotransport regulates intracellular volume and monolayer permeability of trabecular meshwork cells

1995 ◽  
Vol 268 (4) ◽  
pp. C1067-C1074 ◽  
Author(s):  
M. E. O'Donnell ◽  
J. D. Brandt ◽  
F. R. Curry
Keyword(s):  
Trabecular Meshwork ◽  
Ethacrynic Acid ◽  
Vascular Endothelial Cells ◽  
Critical Role ◽  
Cell Types ◽  
Cell Monolayers ◽  
Aqueous Humor Outflow ◽  
Trabecular Meshwork Cells ◽  
Intracellular Volume ◽  
Underlying Mechanisms

The trabecular meshwork (TM) of the eye plays a critical role in modulating intraocular pressure (IOP) through regulation of aqueous humor outflow, although the underlying mechanisms remain unknown. Ethacrynic acid, an agent known to inhibit Na-K-Cl cotransport of a number of cell types, recently has been reported to increase aqueous outflow and lower IOP through an unknown effect on the TM. In vascular endothelial cells and a variety of other cell types, the Na-K-Cl cotransporter functions to regulate intracellular volume. The present study was conducted to evaluate TM cells for the presence of Na-K-Cl cotransport activity and to test the hypothesis that modulation of cotransport activity alters intracellular volume and, consequently, permeability of the TM. We demonstrate here that bovine and human TM cells exhibit robust Na-K-Cl cotransport activity that is inhibited by bumetanide and by ethacrynic acid. Our studies also show that TM cell Na-K-Cl cotransport is modulated by a variety of hormones and neurotransmitters. Inhibition of the cotransporter either by bumetanide, ethacrynic acid, or inhibitory hormones reduces TM intracellular volume, whereas stimulatory hormones increase cell volume. In addition, shrinkage of the cells by hypertonic media stimulates cotransport activity and initiates a subsequent regulatory volume increase. Permeability of TM cell monolayers, assessed as transmonolayer flux of [14C]sucrose, is increased by hypertonicity-induced cell shrinkage and by bumetanide. These findings suggest that Na-K-Cl cotransport of TM cells is of central importance to regulation of intracellular volume and TM permeability. Defects of Na-K-Cl cotransport may underlie the pathophysiology of glaucoma.

scholarly journals The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1074
Author(s):  
Natalia Vacani-Martins ◽  
Marcelo Meuser-Batista ◽  
Carina de Lima Pereira dos Santos ◽  
Alejandro Marcel Hasslocher-Moreno ◽  
Andrea Henriques-Pons
Keyword(s):  
Immune Response ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Clinical Signs ◽  
Cell Types ◽  
Experimental Models ◽  
Chronic Patients ◽  
The Usa ◽  
Multiple Cell ◽  
Underlying Mechanisms

Chagas disease was described more than a century ago and, despite great efforts to understand the underlying mechanisms that lead to cardiac and digestive manifestations in chronic patients, much remains to be clarified. The disease is found beyond Latin America, including Japan, the USA, France, Spain, and Australia, and is caused by the protozoan Trypanosoma cruzi. Dr. Carlos Chagas described Chagas disease in 1909 in Brazil, and hepatomegaly was among the clinical signs observed. Currently, hepatomegaly is cited in most papers published which either study acutely infected patients or experimental models, and we know that the parasite can infect multiple cell types in the liver, especially Kupffer cells and dendritic cells. Moreover, liver damage is more pronounced in cases of oral infection, which is mainly found in the Amazon region. However, the importance of liver involvement, including the hepatic immune response, in disease progression does not receive much attention. In this review, we present the very first paper published approaching the liver’s participation in the infection, as well as subsequent papers published in the last century, up to and including our recently published results. We propose that, after infection, activated peripheral T lymphocytes reach the liver and induce a shift to a pro-inflammatory ambient environment. Thus, there is an immunological integration and cooperation between peripheral and hepatic immunity, contributing to disease control.

scholarly journals Mechanisms linking adipose tissue inflammation to cardiac hypertrophy and fibrosis

2019 ◽  
Vol 133 (22) ◽  
pp. 2329-2344 ◽  
Author(s):  
Sarah R. Anthony ◽  
Adrienne R. Guarnieri ◽  
Anamarie Gozdiff ◽  
Robert N. Helsley ◽  
Albert Phillip Owens ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cardiac Hypertrophy ◽  
Critical Role ◽  
Cell Types ◽  
Anatomical Location ◽  
Brown Adipocytes ◽  
Endocrine Organ ◽  
Inflammatory State ◽  
Multiple Cell ◽  
The Impact

Abstract Adipose tissue is classically recognized as the primary site of lipid storage, but in recent years has garnered appreciation for its broad role as an endocrine organ comprising multiple cell types whose collective secretome, termed as adipokines, is highly interdependent on metabolic homeostasis and inflammatory state. Anatomical location (e.g. visceral, subcutaneous, epicardial etc) and cellular composition of adipose tissue (e.g. white, beige, and brown adipocytes, macrophages etc.) also plays a critical role in determining its response to metabolic state, the resulting secretome, and its potential impact on remote tissues. Compared with other tissues, the heart has an extremely high and constant demand for energy generation, of which most is derived from oxidation of fatty acids. Availability of this fatty acid fuel source is dependent on adipose tissue, but evidence is mounting that adipose tissue plays a much broader role in cardiovascular physiology. In this review, we discuss the impact of the brown, subcutaneous, and visceral white, perivascular (PVAT), and epicardial adipose tissue (EAT) secretome on the development and progression of cardiovascular disease (CVD), with a particular focus on cardiac hypertrophy and fibrosis.

scholarly journals MUNIn (Multiple cell-type UNifying long-range chromatin Interaction detector): a statistical framework for identifying long-range chromatin interactions from multiple cell types

2020 ◽  
Author(s):  
Weifang Liu ◽  
Armen Abnousi ◽  
Qian Zhang ◽  
Yun Li ◽  
Ming Hu ◽  
...  
Keyword(s):  
Long Range ◽  
Spatial Organization ◽  
Critical Role ◽  
Cell Types ◽  
Chromatin Interaction ◽  
Cell Type ◽  
Statistical Framework ◽  
Chromatin Interactions ◽  
The Status ◽  
Multiple Cell

AbstractChromatin spatial organization (interactome) plays a critical role in genome function. Deep understanding of chromatin interactome can shed insights into transcriptional regulation mechanisms and human disease pathology. One essential task in the analysis of chromatin interactomic data is to identify long-range chromatin interactions. Existing approaches, such as HiCCUPS, FitHiC/FitHiC2 and FastHiC, are all designed for analyzing individual cell types. None of them accounts for unbalanced sequencing depths and heterogeneity among multiple cell types in a unified statistical framework. To fill in the gap, we have developed a novel statistical framework MUNIn (Multiple cell-type UNifying long-range chromatin Interaction detector) for identifying long-range chromatin interactions from multiple cell types. MUNIn adopts a hierarchical hidden Markov random field (H-HMRF) model, in which the status (peak or background) of each interacting chromatin loci pair depends not only on the status of loci pairs in its neighborhood region, but also on the status of the same loci pair in other cell types. To benchmark the performance of MUNIn, we performed comprehensive simulation studies and real data analysis, and showed that MUNIn can achieve much lower false positive rates for detecting cell-type-specific interactions (33.1 - 36.2%), and much enhanced statistical power for detecting shared peaks (up to 74.3%), compared to uni-cell-type analysis. Our data demonstrated that MUNIn is a useful tool for the integrative analysis of interactomic data from multiple cell types.

scholarly journals Advanced glycation end-products regulate extracellular matrix-adipocyte metabolic crosstalk in diabetes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Clarissa Strieder-Barboza ◽  
Nicki A. Baker ◽  
Carmen G. Flesher ◽  
Monita Karmakar ◽  
Christopher K. Neeley ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Rho Gtpases ◽  
Cell Types ◽  
Scavenger Receptors ◽  
Advanced Glycation ◽  
Human Diabetes ◽  
Multiple Cell ◽  
Underlying Mechanisms

AbstractThe adipose tissue extracellular matrix (ECM) regulates adipocyte cellular metabolism and is altered in obesity and type 2 diabetes, but mechanisms underlying ECM-adipocyte metabolic crosstalk are poorly defined. Advanced glycation end-product (AGE) formation is increased in diabetes. AGE alter tissue function via direct effects on ECM and by binding scavenger receptors on multiple cell types and signaling through Rho GTPases. Our goal was to determine the role and underlying mechanisms of AGE in regulating human ECM-adipocyte metabolic crosstalk. Visceral adipocytes from diabetic and non-diabetic humans with obesity were studied in 2D and 3D-ECM culture systems. AGE is increased in adipose tissue from diabetic compared to non-diabetic subjects. Glycated collagen 1 and AGE-modified ECM regulate adipocyte glucose uptake and expression of AGE scavenger receptors and Rho signaling mediators, including the DIAPH1 gene, which encodes the human Diaphanous 1 protein (hDia1). Notably, inhibition of hDia1, but not scavenger receptors RAGE or CD36, attenuated AGE-ECM inhibition of adipocyte glucose uptake. These data demonstrate that AGE-modification of ECM contributes to adipocyte insulin resistance in human diabetes, and implicate hDia1 as a potential mediator of AGE-ECM-adipocyte metabolic crosstalk.

scholarly journals Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy

2017 ◽  
Vol 115 (2) ◽  
pp. E180-E189 ◽  
Author(s):  
Christoph Potting ◽  
Christophe Crochemore ◽  
Francesca Moretti ◽  
Florian Nigsch ◽  
Isabel Schmidt ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Critical Role ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Physiological Regulation ◽  
Genome Wide ◽  
Crispr Screen ◽  
Multiple Cell ◽  
Induced Pluripotent ◽  
The Impact

PARKIN, an E3 ligase mutated in familial Parkinson’s disease, promotes mitophagy by ubiquitinating mitochondrial proteins for efficient engagement of the autophagy machinery. Specifically, PARKIN-synthesized ubiquitin chains represent targets for the PINK1 kinase generating phosphoS65-ubiquitin (pUb), which constitutes the mitophagy signal. Physiological regulation of PARKIN abundance, however, and the impact on pUb accumulation are poorly understood. Using cells designed to discover physiological regulators of PARKIN abundance, we performed a pooled genome-wide CRISPR/Cas9 knockout screen. Testing identified genes individually resulted in a list of 53 positive and negative regulators. A transcriptional repressor network including THAP11 was identified and negatively regulates endogenous PARKIN abundance. RNAseq analysis revealed the PARKIN-encoding locus as a prime THAP11 target, and THAP11 CRISPR knockout in multiple cell types enhanced pUb accumulation. Thus, our work demonstrates the critical role of PARKIN abundance, identifies regulating genes, and reveals a link between transcriptional repression and mitophagy, which is also apparent in human induced pluripotent stem cell-derived neurons, a disease-relevant cell type.

scholarly journals CAGEd-oPOSSUM: motif enrichment analysis from CAGE-derived TSSs

2016 ◽  
Author(s):  
David J. Arenillas ◽  
Alistair R.R. Forrest ◽  
Hideya Kawaji ◽  
Timo Lassman ◽  
Wyeth W. Wasserman ◽  
...  
Keyword(s):  
Large Scale ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Specific Cell ◽  
Data Sets ◽  
Transcription Start Sites ◽  
Supplementary Material ◽  
Supplementary Text ◽  
Cap Analysis ◽  
Genomic Regions

AbstractSummaryWith the emergence of large-scale Cap Analysis of Gene Expression (CAGE) data sets from individual labs and the FANTOM consortium, one can now analyze the cis-regulatory regions associated with gene transcription at an unprecedented level of refinement. By coupling transcription factor binding site (TFBS) enrichment analysis with CAGE-derived genomic regions, CAGEd-oPOSSUM can identify TFs that act as key regulators of genes involved in specific mammalian cell and tissue types. The webtool allows for the analysis of CAGE-derived transcription start sites (TSSs) either provided by the user or selected from ~1,300 mammalian samples from the FANTOM5 project with pre-computed TFBS predicted with JASPAR TF binding profiles. The tool helps power insights into the regulation of genes through the study of the specific usage of TSSs within specific cell types and/or under specific conditions.Availability and implementationThe CAGEd-oPOSUM web tool is implemented in Perl, MySQL, and Apache and is available at http://cagedop.cmmt.ubc.ca/CAGEd_oPOSSUM.Supporting InformationSupplementary Text, Figures, and Data are available online at bioRxiv.

scholarly journals A single-cell genomic strategy for alternative transcript start sites identification

2021 ◽  
Author(s):  
Yanling Peng ◽  
Qitong Huang ◽  
Rui Kamada ◽  
Keiko Ozato ◽  
Yubo Zhang ◽  
...  
Keyword(s):  
Single Cell ◽  
Critical Role ◽  
Genomic Analysis ◽  
Cell Types ◽  
Alternative Transcript ◽  
Transcription Start Sites ◽  
Genome Wide ◽  
Alternative Transcription ◽  
A Genome ◽  
Alternative Tsss

Alternative transcription start sites (TSSs) usage plays a critical role in gene transcription regulation in mammals. However, precisely identifying alternative TSSs remains challenging at the genome-wide level. Here, we report a single-cell genomic technology for alternative TSSs annotation and cell heterogeneity detection. In the method, we utilize Fluidigm C1 system to capture individual cells of interest, SMARTer cDNA synthesis kit to recover full-length cDNAs, then dual priming oligonucleotide system to specifically enrich TSSs for genomic analysis. We apply this method to a genome-wide study of alternative TSSs identification in two different IFN-β stimulated mouse embryonic fibroblasts (MEFs). We quantify the performance of our method and find it as accurate as other single cell methods for the detection of TSSs. Our data are also clearly discriminate two IFN-β stimulated MEFs. Moreover, our results indicate 82% expressed genes in these two cell types containing multiple TSSs, which is much higher than previous predictions based on CAGE (58%) or empirical determination (54%) in various cell types. This indicates that alternative TSSs are more pervasive than expected and implies our strategy could position them at an unprecedented sensitivity. It would be helpful for elucidating their biological insights in future.

scholarly journals Exosomes May Be the Potential New Direction of Research in Osteoarthritis Management

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Cheng Ju ◽  
Renfeng Liu ◽  
Yu Zhang ◽  
Feifei Zhang ◽  
Jun Sun ◽  
...  
Keyword(s):  
Critical Role ◽  
Life Quality ◽  
Cell Types ◽  
Biological Molecules ◽  
Lipid Bilayer Membranes ◽  
Surgical Safety ◽  
Potential Efficacy ◽  
Multiple Cell ◽  
Repeated Pain

Osteoarthritis (OA) is a joint degenerative disease, which is prominent in the middle-aged and elderly population, often leading to repeated pain in the joints of patients and seriously affecting the life quality of patients. At present, the treatment of OA mainly depends on the surgery and drug treatment. Nevertheless, these treatments still face many problems, such as surgical safety, complications, and drug side effects. Exosomes can be secreted and released by multiple cell types and have lipid bilayer membranes and contain abundant biological molecules, including proteins, lipids, and nucleic acids. Moreover, exosomes play a critical role in local and distal intercellular and intracellular communication. In recent years, several studies have found that exosomes can regulate the progression of OA and have a potential efficacy for OA treatment. Thus, in this article, we summarize and review the relevant research of exosomes in OA and emphasize the importance of exosomes in the development of OA.

Abstract 15756: Vascular Guidance of Cardiomyocyte Proliferation During Growth and Regeneration

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Paige DeBeneditts ◽  
Anish Karpurapu ◽  
Kyla Brezitski ◽  
Michael C Thomas ◽  
Ravi - Karra
Keyword(s):  
Large Scale ◽  
Nearest Neighbor ◽  
Critical Role ◽  
Cell Types ◽  
Neonatal Mouse ◽  
Angiogenic Factor ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Cardiac Growth ◽  
Multiple Cell

Introduction: Stimulating cardiomyocyte (CM) proliferation is a major strategy for achieving therapeutic heart regeneration. However, heart regeneration requires coordinated interactions of multiple cell types. Because a hallmark of advanced heart failure is vascular rarefaction, the requirement of cardiac endothelial cells (CECs) for cardiac growth and regeneration is of particular importance. Hypothesis: We hypothesized that CECs are required for CM proliferation during growth and regeneration. Methods and Results: We performed a large-scale histologic assessment of neonatal mouse hearts and found the rate of CEC proliferation to shadow CM proliferation over the first 10 days of life. Using a nearest neighbor analysis, we found the fraction of proliferating CECs to be significantly enriched around cycling CMs compared to non-cycling CMs, suggesting that CEC and CM expansion are coupled within a myovascular niche. Single cell sequencing of neonatal mouse hearts after cryoinjury revealed that a majority of these proliferating CECs also express Vegfr2 . To functionally link CEC and CM proliferation, we generated Cdh5-CreER T2 ; Vefgr2 flox/flox mice to genetically delete Vegfr2 from CECs. Compared to mice with intact Vegfr2 , loss of Vegfr2 from CECs in neonatal mice leads to loss of CECs and severely dampens CM proliferation by 4 days (7.01±0.88% vs 0.39±0.35%, p = 7.4x10-4, n = 9),. Interestingly, CM proliferation is attenuated when Vegfr2 is deleted from CECs despite an increase of hypoxia indicators in CMs, signifying that hypoxia-induced CM proliferation is dependent on CECs. In contrast to CEC depletion, treatment of cryoinjured neonatal hearts with AAV encoding the master angiogenic factor, Vegfa can enhance heart regeneration with increased CM cycling in the borderzone (12.6±2.2% vs 5.4±0.4%, p = 0.02, n = 8), reduced scarring of the left ventricle (3.4±1.4% vs 7.6±1.2%, p = 03, n = 16), and improved fractional shortening (51.7±2.5% vs 36.7±4.3%, p = 0.007, n = 14). Conclusions: CEC and CM expansion are spatiotemporally coupled in a myovascular niche during cardiac growth. CECs play a critical role to support CM proliferation and are likely to provide instructive cues that may be leveraged for therapeutic heart regeneration.

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