23 results found
Dahale S, Ruiz-Orera J, Silhavy J, et al., 2022, Cap analysis of gene expression reveals alternative promoter usage in a rat model of hypertension, Life Science Alliance, Vol: 5, ISSN: 2575-1077
The role of alternative promoter usage in tissue-specific gene expression has been well established, however, its role in complex diseases is poorly understood. We performed cap analysis of gene expression (CAGE) sequencing from the left ventricle (LV) of a rat model of hypertension, the spontaneously hypertensive rat (SHR), and a normotensive strain, Brown Norway (BN) to understand the role of alternative promoter usage in complex disease. We identified 26,560 CAGE-defined transcription start sites (TSS) in the rat LV, including 1,970 novel cardiac TSSs. We identified 28 genes with alternative promoter usage between SHR and BN, which could lead to protein isoforms differing at the amino terminus between two strains and 475 promoter switching events altering the length of the 5’ UTR. We found that the shift in Insr promoter usage was significantly associated with insulin levels and blood pressure within a panel of HXB/BXH recombinant inbred rat strains, suggesting that hyperinsulinemia due to insulin resistance might lead to hypertension in SHR. Our study provides a preliminary evidence of alternative promoter usage in complex diseases.
Ahmetaj-Shala B, Ricky V, Santosh A, et al., 2020, Cardiorenal tissues express SARS-CoV-2 entry genes and basigin (BSG/CD147) increases with age in endothelial cells, JACC: Basic to Translational Science, Vol: 5, Pages: 1111-1123, ISSN: 2452-302X
Objectives: To obtain mechanistic insight into COVID-19 within a cardiovascular setting.Background: Thrombosis and vascular dysfunction are part of the complex pathology seen in severe COVID-19 and advancing age is the most significant risk factor. Little is known about age and expression of pathways utilised by the COVID-19 virus, SARS-CoV-2, in cardiovascular tissues.Methods: We used publicly available databases (GTEx, GEO and Array Express) to investigate gene expression levels, in adult tissues, of the two putative SARS-CoV-2 receptors, ACE2 and BSG along with a selected range of genes thought to be involved in virus binding/processing. Our analysis included; vessels (aorta and coronary artery), heart (atrial appendage and left ventricle), kidney (cortex), whole blood, lung, colon and spleen along with endothelial cells, nasal and bronchial epithelium and peripheral blood mononuclear cells. Gene expression levels were then analysed for age associations.Results: We found: (i) cardiovascular tissues/endothelial cells express the required genes for SARS-CoV-2 infection, (ii) SARS-CoV-2 receptor pathways, ACE2/TMPRSS2 and BSG/PPIB(A) polarise to lung/epithelium and vessel/endothelium respectively, (iii) expression of host genes are relatively stable with age and (iv) notable exceptions are ACE2 which decreases with age in some tissues and BSG which increases with age in endothelial cells.Conclusion: Our data identifies a positive correlation of BSG with age in endothelial cells. Since BSG is utilised by other pathogens and is implicated in a range of cardiovascular disease, our observations may have relevance to our understanding of mechanisms associated with other pathogens and in the diseases associated with aging respectively.
Watson S, Duff J, Bardi I, et al., 2019, Biomimetic electromechanical stimulation to maintain adult myocardial slices in vitro, Nature Communications, Vol: 10, ISSN: 2041-1723
Adult cardiac tissue undergoes a rapid process of dedifferentiation when cultured outside the body. The in vivo environment, particularly constant electromechanical stimulation, is fundamental to the regulation of cardiac structure and function. We investigated the role of electromechanical stimulation in preventing culture-induced dedifferentiation of adult cardiac tissue using rat, rabbit and human heart failure myocardial slices. Here we report that the application of a preload equivalent to sarcomere length (SL) = 2.2 μm is optimal for the maintenance of rat myocardial slice structural, functional and transcriptional properties at 24 h. Gene sets associated with the preservation of structure and function are activated, while gene sets involved in dedifferentiation are suppressed. The maximum contractility of human heart failure myocardial slices at 24 h is also optimally maintained at SL = 2.2 μm. Rabbit myocardial slices cultured at SL = 2.2 μm remain stable for 5 days. This approach substantially prolongs the culture of adult cardiac tissue in vitro.
De Vas MG, Garstang MG, Joshi SS, et al., 2019, <i>De novo</i> variants in population constrained fetal brain enhancers and intellectual disability, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>The genetic aetiology of a major fraction of patients with intellectual disability (ID) remains unknown. <jats:italic>De novo</jats:italic> mutations (DNMs) in protein-coding genes explain up to 40% of cases, but the potential role of regulatory DNMs is still poorly understood.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We sequenced 70 whole genomes from 24 ID probands and their unaffected parents and analyzed 30 previously sequenced genomes from exome-negative ID probands.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We found that DNVs were selectively enriched in fetal brain-specific enhancers that show purifying selection in human population. DNV containing enhancers were associated with genes that show preferential expression in the pre-frontal cortex, have been previously implicated in ID or related disorders, and exhibit intolerance to loss of function variants. DNVs from ID probands preferentially disrupted putative binding sites of neuronal transcription factors, as compared to DNVs from healthy individuals and most showed allele-specific enhancer activity. In addition, we identified recurrently mutated enhancer clusters that regulate genes involved in nervous system development (<jats:italic>CSMD1</jats:italic>, <jats:italic>OLFM1</jats:italic> and <jats:italic>POU3F3)</jats:italic>. Moreover, CRISPR-based perturbation of a DNV-containing enhancer caused <jats:italic>CSMD1</jats:italic> overexpression and abnormal expression of neurodevelopmental regulators.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our results, therefore, provide new evidence to indicate that DNVs in constrained fetal brain-speci
Rajani RM, Quick S, Ruigrok SR, et al., 2018, Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats, Science Translational Medicine, Vol: 10, Pages: 1-12, ISSN: 1946-6234
Dementia is a major social and economic problem for our aging population. One of the most common of dementia in the elderly is cerebral small vessel disease (SVD). Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage. Hypertension is suggested as the cause of sporadic SVD, but a recent alternative hypothesis invokes dysfunction of the blood-brain barrier as the primary cause. In a rat model of SVD, we show that endothelial cell (EC) dysfunction is the first change in development of the disease. Dysfunctional ECs secrete heat shock protein 90α, which blocks oligodendroglial differentiation, contributing to impaired myelination. Treatment with EC-stabilizing drugs reversed these EC and oligodendroglial pathologies in the rat model. EC and oligodendroglial dysfunction were also observed in humans with early, asymptomatic SVD pathology. We identified a loss-of-function mutation in ATPase11B, which caused the EC dysfunction in the rat SVD model, and a single-nucleotide polymorphism in ATPase11B that was associated with white matter abnormalities in humans with SVD. We show that EC dysfunction is a cause of SVD white matter vulnerability and provide a therapeutic strategy to treat and reverse SVD in the rat model, which may also be of relevance to human SVD.
Black HA, Parry D, Atanur SS, et al., 2016, De novo mutations in autosomal recessive congenital malformations, Genetics in Medicine, Vol: 18, Pages: 1325-1326, ISSN: 1098-3600
Abdelmagid N, Bereczky-Veress B, Atanur S, et al., 2016, Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis, PLOS One, Vol: 11, ISSN: 1932-6203
Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines—generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89–174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11–2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.
Zhao L, Oliver E, Maratou K, et al., 2015, The zinc transporter, ZIP12, regulates the pulmonary vascular response to chronic hypoxia, Nature, Vol: 524, Pages: 356-360, ISSN: 0028-0836
The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension1, 2, 3. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.
Wang J, Ma MCJ, Mennie AK, et al., 2015, Systems Biology With High-Throughput Sequencing Reveals Genetic Mechanisms Underlying the Metabolic Syndrome in the Lyon Hypertensive Rat, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 8, Pages: 316-326, ISSN: 1942-325X
Johnson MD, Mueller M, Adamowicz-Brice M, et al., 2014, Genetic Analysis of the Cardiac Methylome at Single Nucleotide Resolution in a Model of Human Cardiovascular Disease, PLOS GENETICS, Vol: 10, ISSN: 1553-7404
Baud A, Guryev V, Hummel O, et al., 2014, Genomes and phenomes of a population of outbred rats and its progenitors, Scientific Data, Vol: 1
Finding genetic variants that contribute to phenotypic variation is one of the main challenges of modern genetics. We used an outbred population of rats (Heterogeneous Stock, HS) in a combined sequence-based and genetic mapping analysis to identify sequence variants and genes contributing to complex traits of biomedical relevance. Here we describe the sequences of the eight inbred progenitors of the HS and the variants that segregate between them. We report the genotyping of 1,407 HS rats, and the collection from 2,006 rats of 195 phenotypic measures that are relevant to models of anxiety, type 2 diabetes, hypertension and osteoporosis. We make available haplotype dosages for the 1,407 genotyped rats, since genetic mapping in the HS is best carried out by reconstructing each HS chromosome as a mosaic of the progenitor genomes. Finally, we have deposited an R object that makes it easy to incorporate our sequence data into any genetic study of HS rats. Our genetic data are available for both Rnor3.4 and Rnor5.0 rat assemblies.
Ma MCJ, Atanur SS, Aitman TJ, et al., 2014, Genomic structure of nucleotide diversity among Lyon rat models of metabolic syndrome, BMC Genomics, Vol: 15, ISSN: 1471-2164
BackgroundThe metabolic syndrome (MetS), a complex disorder involving hypertension, obesity, dyslipidemia and insulin resistance, is a major risk factor for heart disease, stroke, and diabetes. The Lyon Hypertensive (LH), Lyon Normotensive (LN) and Lyon Low-pressure (LL) rats are inbred strains simultaneously derived from a common outbred Sprague Dawley colony by selection for high, normal, and low blood pressure, respectively. Further studies found that LH is a MetS susceptible strain, while LN is resistant and LL has an intermediate phenotype. Whole genome sequencing determined that, while the strains are phenotypically divergent, they are nearly 98% similar at the nucleotide level. Using the sequence of the three strains, we applied an approach that harnesses the distribution of Observed Strain Differences (OSD), or nucleotide diversity, to distinguish genomic regions of identity-by-descent (IBD) from those with divergent ancestry between the three strains. This information was then used to fine-map QTL identified in a cross between LH and LN rats in order to identify candidate genes causing the phenotypes.ResultsWe identified haplotypes that, in total, contain at least 95% of the identifiable polymorphisms between the Lyon strains that are likely of differing ancestral origin. By intersecting the identified haplotype blocks with Quantitative Trait Loci (QTL) previously identified in a cross between LH and LN strains, the candidate QTL regions have been narrowed by 78%. Because the genome sequence has been determined, we were further able to identify putative functional variants in genes that are candidates for causing the QTL.ConclusionsWhole genome sequence analysis between the LH, LN, and LL strains identified the haplotype structure of these three strains and identified candidate genes with sequence variants predicted to affect gene function. This approach, merged with additional integrative genetics approaches, will likely lead to novel mechanisms underlying
Vandrovcova J, Thomas ERA, Atanur SS, et al., 2013, The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia, GENETICS IN MEDICINE, Vol: 15, Pages: 948-957, ISSN: 1098-3600
Thomas ERA, Atanur SS, Norsworthy PJ, et al., 2013, Identification and biochemical analysis of a novel APOB mutation that causes autosomal dominant hypercholesterolemia., Molecular Genetics and Genomic Medicine, Vol: 1, Pages: 155-161, ISSN: 2324-9269
Patients with autosomal dominant hypercholesterolemia (ADH) have a high risk of developing cardiovascular disease that can be effectively treated using statin drugs. Molecular diagnosis and family cascade screening is recommended for early identification of individuals at risk, but up to 40% of families have no mutation detected in known genes. This study combined linkage analysis and exome sequencing to identify a novel variant in exon 3 of APOB (Arg50Trp). Mass spectrometry established that low-density lipoprotein (LDL) containing Arg50Trp APOB accumulates in the circulation of affected individuals, suggesting defective hepatic uptake. Previously reported mutations in APOB causing ADH have been located in exon 26. This is the first report of a mutation outside this region causing this phenotype, therefore, more extensive screening of this large and highly polymorphic gene may be necessary in ADH families. This is now feasible due to the high capacity of recently available sequencing platforms.
Atanur SS, Garcia-Diaz A, Maratou K, et al., 2013, Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat., Cell
Pillai R, Waghulde H, Nie Y, et al., 2013, Isolation and high-throughput sequencing of two closely linked epistatic hypertension susceptibility loci with a panel of bicongenic strains, PHYSIOLOGICAL GENOMICS, Vol: 45, Pages: 729-736, ISSN: 1094-8341
Baud A, Hermsen R, Guryev V, et al., 2013, Combined sequence-based and genetic mapping analysis of complex traits in outbred rats, NATURE GENETICS, Vol: 45, Pages: 767-+, ISSN: 1061-4036
Hull RP, Srivastava PK, D'Souza Z, et al., 2013, Combined ChIP-Seq and transcriptome analysis identifies AP-1/JunD as a primary regulator of oxidative stress and IL-1 beta synthesis in macrophages, BMC GENOMICS, Vol: 14, ISSN: 1471-2164
Johnson MD, Mueller M, Game L, et al., 2012, Single Nucleotide Analysis of Cytosine Methylation by Whole-Genome Shotgun Bisulfite Sequencing
Unlike other methods to assess methylation, whole-genome shotgun bisulfite sequencing is used to generate quantitative genome-wide methylation profiles at single-nucleotide resolution. As described in this unit, this method allows for the quantitative measurement of methylation at each cytosine base by treatment of genomic DNA with sodium bisulfite followed by sequencing and alignment of the reads to a reference genome. Curr. Protoc. Mol. Biol. 99:21.23.1-21.23.28. © 2012 by John Wiley & Sons, Inc.
Morrissey C, Grieve IC, Heinig M, et al., 2011, Integrated genomic approaches to identification of candidate genes underlying metabolic and cardiovascular phenotypes in the spontaneously hypertensive rat, PHYSIOLOGICAL GENOMICS, Vol: 43, Pages: 1207-1218, ISSN: 1094-8341
Atanur SS, Birol I, Guryev V, et al., 2010, The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance, GENOME RESEARCH, Vol: 20, Pages: 791-803, ISSN: 1088-9051
Patil DP, Atanur S, Dhotre DP, et al., 2009, Generation, annotation, and analysis of ESTs from midgut tissue of adult female Anopheles stephensi mosquitoes, BMC Genomics, Vol: 10, Pages: 386-386, ISSN: 1471-2164
Rangrez AY, Dayananda KM, Atanur S, et al., 2006, Detection of Conjugation Related Type Four Secretion Machinery in Aeromonas culicicola, PLoS ONE, Vol: 1, Pages: e115-e115
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.