155 results found
Chen H, Chew G, Devapragash N, et al., 2022, The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis., Nat Commun, Vol: 13
Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac tissue remodeling. Recent evidence implicates monocytes/macrophages in the etiopathology of cardiac fibrosis, but giving their heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis, targeting these cells has been challenging. Here we focus on WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that myeloid specific deletion of WWP2 reduces cardiac fibrosis in hypertension-induced NICM. By using single cell RNA sequencing analysis of immune cells in the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase of NICM that is driven by Ccl5-expressing Ly6chigh monocytes. Among cardiac macrophage subtypes, WWP2 dysfunction primarily affects Ly6chigh monocytes via modulating Ccl5, and consequentially macrophage infiltration and activation, which contributes to reduced myofibroblast trans-differentiation. WWP2 interacts with transcription factor IRF7, promoting its non-degradative mono-ubiquitination, nuclear translocation and transcriptional activity, leading to upregulation of Ccl5 at transcriptional level. We identify a pro-fibrogenic macrophage subtype in non-ischemic cardiomyopathy, and demonstrate that WWP2 is a key regulator of IRF7-mediated Ccl5/Ly6chigh monocyte axis in heart fibrosis.
Lee LM, Christodoulou EG, Shyamsunder P, et al., 2022, A novel network pharmacology approach for leukaemia differentiation therapy using Mogrify (R), ONCOGENE, ISSN: 0950-9232
Ji J, Anwar M, Petretto E, et al., 2022, PPMS: a framework to profile primary microRNAs from single-cell RNA-sequencing datasets, Briefings in Bioinformatics, ISSN: 1467-5463
Motivation:Single-cell/nuclei RNA sequencing (scRNA-seq) technologies can simultaneously quantify gene expression in thousands of cells across the genome. However, the majority of the non-coding RNAs, such as microRNAs (miRNAs), cannot currently be profiled at the same scale. MiRNAs are a class of small non-coding RNAs and play an important role in gene regulation. MiRNAs originate from the processing of primary transcripts, known as primary-microRNAs (pri-miRNAs). The pri-miRNA transcripts, independent of their cognate miRNAs, can also function as long non-coding RNAs, code for micropeptides or even interact with DNA, acting like enhancers. Therefore, it is apparent that the significance of scRNA-seq pri-miRNA profiling expands beyond using pri-miRNA as proxies of mature miRNAs. However, there are no computational methods that allow profiling and quantification of pri-miRNAs at the single-cell type resolution.Results:We have developed a simple yet effective computational framework to Profile Pri-MiRNAs from Single-cell RNA-sequencing datasets (PPMS). Based on user input, PPMS can profile pri-miRNAs at cell-type resolution. PPMS can be applied to both newly produced and publicly available datasets obtained via single cell or single nuclei RNA-seq. It allows users to (i) investigate the distribution of pri-miRNAs across cell types and cell states and (ii) establish a relationship between the number of cells/reads sequenced and the detection of pri-miRNAs. Here, to demonstrate its efficacy, we have applied PPMS to publicly available scRNA-seq data generated from (a) individual chambers (ventricles and atria) of the human heart, (b) human pluripotent stem cells during their differentiation into cardiomyocytes (the heart beating cells) and (c) hiPSCs-derived cardiomyocytes infected with SARS-CoV2 virus. Availability and implementation:PPMS is free to use under a GNU license and is available to download from (GitHub link: https://github.com/SrivastavaLab-ICL/PPMS)
Zhou J, Pang J, Tripathi M, et al., 2022, Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression, Nature Communications, Vol: 13, Pages: 1-14, ISSN: 2041-1723
Spermidine is a natural polyamine that has health benefits and extends life span in several species. Deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) are key enzymes that utilize spermidine to catalyze the post-translational hypusination of the translation factor EIF5A (EIF5AH). Here, we have found that hepatic DOHH mRNA expression is decreased in patients and mice with non-alcoholic steatohepatitis (NASH), and hepatic cells treated with fatty acids. The mouse and cell culture models of NASH have concomitant decreases in Eif5aH and mitochondrial protein synthesis which leads to lower mitochondrial activity and fatty acid β-oxidation. Spermidine treatment restores EIF5AH, partially restores protein synthesis and mitochondrial function in NASH, and prevents NASH progression in vivo. Thus, the disrupted DHPS-DOHH-EIF5AH pathway during NASH represents a therapeutic target to increase hepatic protein synthesis and mitochondrial fatty acid oxidation (FAO) and prevent NASH progression.
Francis C, Futschik M, Huang J, et al., 2022, Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities, Nature Communications, Vol: 13, ISSN: 2041-1723
Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.
Behmoaras J, 2022, Immunolipidomics reveals a globoside network during the resolution of pro-inflammatory response in human macrophages, Frontiers in Immunology, Vol: 13, ISSN: 1664-3224
Toll-like receptor 4 (TLR4)-mediated changes in macrophages reshape intracellular lipid pools to coordinate an effective innate immune response. Although this has been previously well-studied in different model systems, it remains incompletely understood in primary human macrophages. Here we report time-dependent lipidomic and transcriptomic responses to lipopolysaccharide (LPS) in primary human macrophages from healthy donors. We grouped the variation of ~200 individual lipid species measured by LC-MS/MS into eight temporal clusters. Among all other lipids, glycosphingolipids (glycoSP) and cholesteryl esters (CE) showed a sharp increase during the resolution phase (between 8h or 16h post LPS). GlycoSP, belonging to the globoside family (Gb3 and Gb4), showed the greatest inter-individual variability among all lipids quantified. Integrative network analysis between GlycoSP/CEs levels and genome-wide transcripts, identified Gb4 d18:1/16:0 and CE 20:4 association with subnetworks enriched for T cell receptor signaling (PDCD1, CD86, PTPRC, CD247, IFNG) and DC-SIGN signaling (RAF1, CD209), respectively. Our findings reveal Gb3 and Gb4 globosides as sphingolipids associated with the resolution phase of inflammatory response in human macrophages.
Kumar P, Lim A, Hazirah SN, et al., 2022, Single-cell transcriptomics and surface epitope detection in human brain epileptic lesions identifies pro-inflammatory signaling, NATURE NEUROSCIENCE, Vol: 25, Pages: 956-+, ISSN: 1097-6256
Yap L, Chong LY, Tan C, et al., 2021, Significant Reduction in Ventricular Tachyarrhythmia After Myocardial Infarction in Cardiovascular Progenitors Transplanted Pig Hearts, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Huang KY, Petretto E, 2021, Cross-species integration of single-cell RNA-seq resolved alveolar-epithelial transitional states in idiopathic pulmonary fibrosis, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 321, Pages: L491-L506, ISSN: 1040-0605
Sparks MA, Dilmen E, Ralph DL, et al., 2021, Vascular control of kidney epithelial transporters., Am J Physiol Renal Physiol, Vol: 320, Pages: F1080-F1092
A major pathway in hypertension pathogenesis involves direct activation of ANG II type 1 (AT1) receptors in the kidney, stimulating Na+ reabsorption. AT1 receptors in tubular epithelia control expression and stimulation of Na+ transporters and channels. Recently, we found reduced blood pressure and enhanced natriuresis in mice with cell-specific deletion of AT1 receptors in smooth muscle (SMKO mice). Although impaired vasoconstriction and preserved renal blood flow might contribute to exaggerated urinary Na+ excretion in SMKO mice, we considered whether alterations in Na+ transporter expression might also play a role; therefore, we carried out proteomic analysis of key Na+ transporters and associated proteins. Here, we show that levels of Na+-K+-2Cl- cotransporter isoform 2 (NKCC2) and Na+/H+ exchanger isoform 3 (NHE3) are reduced at baseline in SMKO mice, accompanied by attenuated natriuretic and diuretic responses to furosemide. During ANG II hypertension, we found widespread remodeling of transporter expression in wild-type mice with significant increases in the levels of total NaCl cotransporter, phosphorylated NaCl cotransporter (Ser71), and phosphorylated NKCC2, along with the cleaved, activated forms of the α- and γ-epithelial Na+ channel. However, the increases in α- and γ-epithelial Na+ channel with ANG II were substantially attenuated in SMKO mice. This was accompanied by a reduced natriuretic response to amiloride. Thus, enhanced urinary Na+ excretion observed after cell-specific deletion of AT1 receptors from smooth muscle cells is associated with altered Na+ transporter abundance across epithelia in multiple nephron segments. These findings suggest a system of vascular-epithelial in the kidney, modulating the expression of Na+ transporters and contributing to the regulation of pressure natriuresis.NEW & NOTEWORTHY The use of drugs to block the renin-angiotensin system to reduce blood pressure is common. However, the precise m
Tay H, Andre H, Chrysostomou V, et al., 2021, Retina Specific Laminin 523 Drives Differentiation of Pluripotent Human Stem Cells to Photoreceptor Progenitors Promoting Retina Function, Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Grubman A, Choo XY, Chew G, et al., 2021, Transcriptional signature in microglia associated with Aβ plaque phagocytosis, Nature Communications, Vol: 12, ISSN: 2041-1723
The role of microglia cells in Alzheimer's disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here, we isolated amyloid plaque-containing (using labelling with methoxy-XO4, XO4+) and non-containing (XO4-) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4+ microglial transcriptomes demonstrated dysregulated expression of genes associated with late onset AD. We further showed that the transcriptional program associated with XO4+ microglia from mice is present in a subset of human microglia isolated from brains of individuals with AD. XO4- microglia displayed transcriptional signatures associated with accelerated ageing and contained more intracellular post-synaptic material than XO4+ microglia, despite reduced active synaptosome phagocytosis. We identified HIF1α as potentially regulating synaptosome phagocytosis in vitro using primary human microglia, and BV2 mouse microglial cells. Together, these findings provide insight into molecular mechanisms underpinning the functional diversity of microglia in AD.
Ciconte G, Monasky MM, Santinelli V, et al., 2021, Brugada syndrome genetics is associated with phenotype severity, EUROPEAN HEART JOURNAL, Vol: 42, Pages: 1082-1090, ISSN: 0195-668X
Kaur A, Lim JYS, Sepramaniam S, et al., 2021, WNT inhibition creates a BRCA-like state in Wnt-addicted cancer, EMBO MOLECULAR MEDICINE, Vol: 13, ISSN: 1757-4676
Harmston N, Lim JYS, Arques O, et al., 2021, Widespread Repression of Gene Expression in Cancer by a Wnt/beta-Catenin/MAPK Pathway, CANCER RESEARCH, Vol: 81, Pages: 464-475, ISSN: 0008-5472
Lovisari F, Roncon P, Soukoupova M, et al., 2021, Implication of sestrin3 in epilepsy and its comorbidities, BRAIN COMMUNICATIONS, Vol: 3
Kamaraj US, Chen J, Katwadi K, et al., 2020, EpiMogrify Models H3K4me3 Data to Identify Signaling Molecules that Improve Cell Fate Control and Maintenance, CELL SYSTEMS, Vol: 11, Pages: 509-+, ISSN: 2405-4712
Liu S, Harmston N, Glaser TL, et al., 2020, Wnt-regulated lncRNA discovery enhanced by in vivo identification and CRISPRi functional validation, GENOME MEDICINE, Vol: 12, ISSN: 1756-994X
Pereira M, Ko J-H, Logan J, et al., 2020, A trans-eQTL network regulates osteoclast multinucleation and bone mass, eLife, Vol: 9, ISSN: 2050-084X
Functional characterisation of cell-type-specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a trans-regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene Bcat1 and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (Pik3cb-/-, Atp8b2+/-, Igsf8-/-, Eml1-/-, Appl2-/-, Deptor-/-) and myeloid-specific Slc40a1 knockout mice displayed abnormal bone phenotypes. We report opposing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast multinucleation and bone mass.
Yap L, Wang J-W, Moreno-Moral A, et al., 2020, In Vivo Generation of Post-infarct Human Cardiac Muscle by Laminin-Promoted Cardiovascular Progenitors (vol 26, 3231.e1, 2019), CELL REPORTS, Vol: 31, ISSN: 2211-1247
Jupp B, Pitzoi S, Petretto E, et al., 2020, Impulsivity is a heritable trait in rodents and associated with a novel quantitative trait locus on chromosome 1, SCIENTIFIC REPORTS, Vol: 10, ISSN: 2045-2322
Zhang S, Reljic B, Liang C, et al., 2020, Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
Guo J, Rackham OJL, Sandholm N, et al., 2020, Whole-Genome Sequencing of Finnish Type 1 Diabetic Siblings Discordant for Kidney Disease Reveals DNA Variants associated with Diabetic Nephropathy, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 31, Pages: 309-323, ISSN: 1046-6673
Ding Q, Tan ALM, Parra EJ, et al., 2020, Genome-wide meta-analysis associates GPSM1 with type 2 diabetes, a plausible gene involved in skeletal muscle function, JOURNAL OF HUMAN GENETICS, Vol: 65, Pages: 411-420, ISSN: 1434-5161
Idris M, Harmston N, Petretto E, et al., 2019, Broad regulation of gene isoform expression by Wnt signaling in cancer, RNA, Vol: 25, Pages: 1696-1713, ISSN: 1355-8382
Grubman A, Chew G, Ouyang JF, et al., 2019, A single-cell atlas of entorhinal cortex from individuals with Alzheimer's disease reveals cell-type-specific gene expression regulation, NATURE NEUROSCIENCE, Vol: 22, Pages: 2087-+, ISSN: 1097-6256
Dixit P, Anwar M, Saif J, et al., 2019, Impaired secretion of clusterin in pericardial fluid of diabetics, a deleterious outcome for the cardiac micro-vasculature, Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 3912-3912, ISSN: 0195-668X
Chew G, Petretto E, 2019, Transcriptional Networks of Microglia in Alzheimer's Disease and Insights into Pathogenesis, GENES, Vol: 10
Chen H, Moreno-Moral A, Pesce F, et al., 2019, Author Correction: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling, Nature Communications, Vol: 10, ISSN: 2041-1723
Laaniste L, Srivastava P, Stylianou T, et al., 2019, Integrated systems-genetic analyses reveal a network target for delaying glioma progression, Annals of Clinical and Translational Neurology, Vol: 6, Pages: 1616-1638, ISSN: 2328-9503
ObjectiveTo identify a convergent, multitarget proliferation characteristic for astrocytoma transformation that could be targeted for therapy discovery.MethodsUsing an integrated functional genomics approach, we prioritized networks associated with astrocytoma progression using the following criteria: differential co‐expression between grade II and grade III IDH1‐mutated and 1p/19q euploid astrocytomas, preferential enrichment for genetic risk to cancer, association with patient survival and sample‐level genomic features. Drugs targeting the identified multitarget network characteristic for astrocytoma transformation were computationally predicted using drug transcriptional perturbation data and validated using primary human astrocytoma cells.ResultsA single network, M2, consisting of 177 genes, was associated with glioma progression on the basis of the above criteria. Functionally, M2 encoded physically interacting proteins regulating cell cycle processes and analysis of genome‐wide gene‐regulatory interactions using mutual information and DNA–protein interactions revealed the known regulators of cell cycle processes FoxM1, B‐Myb, and E2F2 as key regulators of M2. These results suggest functional disruption of M2 via gene mutation or altered expression as a convergent pathway regulating astrocytoma transformation. By considering M2 as a multitarget drug target regulating astrocytoma transformation, we identified several drugs that are predicted to restore M2 expression in anaplastic astrocytoma toward its low‐grade profile and of these, we validated the known antiproliferative drug resveratrol as down‐regulating multiple nodes of M2 including at nanomolar concentrations achievable in human cerebrospinal fluid by oral dosing.InterpretationOur results identify M2 as a multitarget network characteristic for astrocytoma progression and encourage M2‐based drug screening to identify new compounds for preventing glioma transformation.
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