146 results found
Huang KY, Petretto E, 2021, Cross-species integration of single-cell RNA-seq resolved alveolar-epithelial transitional states in idiopathic pulmonary fibrosis., Am J Physiol Lung Cell Mol Physiol, Vol: 321, Pages: L491-L506
Single-cell transcriptomics analyses of the fibrotic lung uncovered two cell states critical to lung injury recovery in the alveolar epithelium-a reparative transitional cell state in the mouse and a disease-specific cell state (KRT5-/KRT17+) in human idiopathic pulmonary fibrosis (IPF). The murine transitional cell state lies between the differentiation from type 2 (AT2) to type 1 pneumocyte (AT1), and the human KRT5-/KRT17+ cell state may arise from the dysregulation of this differentiation process. We review major findings of single-cell transcriptomics analyses of the fibrotic lung and reanalyzed data from seven single-cell RNA sequencing studies of human and murine models of IPF, focusing on the alveolar epithelium. Our comparative and cross-species single-cell transcriptomics analyses allowed us to further delineate the differentiation trajectories from AT2 to AT1 and AT2 to the KRT5-/KRT17+ cell state. We observed AT1 cells in human IPF retain the transcriptional signature of the murine transitional cell state. Using pseudotime analysis, we recapitulated the differentiation trajectories from AT2 to AT1 and from AT2 to KRT5-/KRT17+ cell state in multiple human IPF studies. We further delineated transcriptional programs underlying cell-state transitions and determined the molecular phenotypes at terminal differentiation. We hypothesize that in addition to the reactivation of developmental programs (SOX4, SOX9), senescence (TP63, SOX4) and the Notch pathway (HES1) are predicted to steer intermediate progenitors to the KRT5-/KRT17+ cell state. Our analyses suggest that activation of SMAD3 later in the differentiation process may explain the fibrotic molecular phenotype typical of KRT5-/KRT17+ cells.
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
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.
Chen H, Moreno-Moral A, Pesce F, et al., 2019, WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling, Nature Communications, Vol: 10, Pages: 1-19, ISSN: 2041-1723
Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.
Aday S, Halevy I, Anwar M, et al., 2019, Development of Bioinspired Synthetic Exosomes With Proangiogenic Potential, 14th Annual American-Heart-Association's Basic Cardiovascular Sciences (BCVS) Scientific Sessions - Integrative Approaches to Complex Cardiovascular Diseases, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7330
Besnier M, Shantikumar S, Anwar M, et al., 2019, miR-15a/-16 inhibit angiogenesis by targeting the Tie2 coding sequence: Therapeutic potential of a miR-15a/16 decoy system in limb ischemia., Molecular Therapy : Nucleic Acids, Vol: 17, Pages: 49-62, ISSN: 2162-2531
MicroRNA-15a (miR-15a) and miR-16, which are transcribed from the miR-15a/miR-16-1 cluster, inhibit post-ischemic angiogenesis. MicroRNA (miRNA) binding to mRNA coding sequences (CDSs) is a newly emerging mechanism of gene expression regulation. We aimed to (1) identify new mediators of the anti-angiogenic action of miR-15a and -16, (2) develop an adenovirus (Ad)-based miR-15a/16 decoy system carrying a luciferase reporter (Luc) to both sense and inhibit miR-15a/16 activity, and (3) investigate Ad.Luc-Decoy-15a/16 therapeutic potential in a mouse limb ischemia (LI) model. LI increased miR-15a and -16 expression in mouse muscular endothelial cells (ECs). The miRNAs also increased in cultured human umbilical vein ECs (HUVECs) exposed to serum starvation, but not hypoxia. Using bioinformatic tools and luciferase activity assays, we characterized miR-15a and -16 binding to Tie2 CDS. In HUVECs, miR-15a or -16 overexpression reduced Tie2 at the protein, but not the mRNA, level. Conversely, miR-15a or -16 inhibition improved angiogenesis in a Tie2-dependent manner. Local Ad.Luc-Decoy-15a/16 delivery increased Tie2 levels in ischemic skeletal muscle and improved post-LI angiogenesis and perfusion recovery, with reduced toe necrosis. Bioluminescent imaging (in vivo imaging system [IVIS]) provided evidence that the Ad.Luc-Decoy-15a/16 system responds to miR-15a/16 increases. In conclusion, we have provided novel mechanistic evidence of the therapeutic potential of local miR-15a/16 inhibition in LI.
Bardile CF, Garcia-Miralles M, Caron NS, et al., 2019, Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 116, Pages: 9622-9627, ISSN: 0027-8424
Douros JD, Niu J, Sdao S, et al., 2019, Sleeve gastrectomy rapidly enhances islet function independently of body weight, JCI INSIGHT, Vol: 4
Yap L, Wang J-W, Moreno-Moral A, et al., 2019, In Vivo Generation of Post-infarct Human Cardiac Muscle by Laminin-Promoted Cardiovascular Progenitors, CELL REPORTS, Vol: 26, Pages: 3231-+, ISSN: 2211-1247
Ford KL, Anwar M, Heys R, et al., 2019, Optimisation of laboratory methods for whole transcriptomic RNA analyses in human left ventricular biopsies and blood samples of clinical relevance, PLoS ONE, Vol: 14, ISSN: 1932-6203
This study aimed to optimise techniques for whole transcriptome and small RNA analyses on clinical tissue samples from patients with cardiovascular disease. Clinical samples often represent a particular challenge to extracting RNA of sufficient quality for robust RNA sequencing analysis, and due to availability, it is rarely possible to optimise techniques on the samples themselves. Therefore, we have used equivalent samples from pigs undergoing cardiopulmonary bypass surgery to test different protocols for optimal RNA extraction, and then validated the protocols in human samples. Here we present an assessment of the quality and quantity of RNA obtained using a variety of commercially-available RNA extraction kits on both left ventricular biopsies and blood plasma. RNA extraction from these samples presents different difficulties; left ventricular biopsies are small and fibrous, while blood plasma has a low RNA content. We have validated our optimised extraction techniques on human clinical samples collected as part of the ARCADIA (Association of non-coding RNAs with Coronary Artery Disease and type 2 Diabetes) cohort study, resulting in successful whole transcriptome and small RNA sequencing of human left ventricular tissue.
Ooi J, Langley SR, Xu X, et al., 2019, Unbiased Profiling of Isogenic Huntington Disease hPSC-Derived CNS and Peripheral Cells Reveals Strong Cell-Type Specificity of CAG Length Effects, CELL REPORTS, Vol: 26, Pages: 2494-+, ISSN: 2211-1247
Behmoaras J, Petretto E, 2019, Cell function in disease: there are more than two parties at play, Annals of the Rheumatic Diseases, Vol: 78, ISSN: 0003-4967
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