Taranjit Singh RaiUlster University · Biomedical Sciences Research Institute
Taranjit Singh Rai
Doctor of Philosophy
About
78
Publications
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Introduction
We are interested in studying cellular senescence, a process of growth arrest of cells that encounter unscheduled stress. Senescent cells accumulate in tissues of humans and other organisms with age. Cellular senescence is thought to promote cell and tissue ageing. Cellular senescence occurs in conjunction with chromatin changes and epigenetic changes. It is crucial to understand how chromatin is maintained in long-term proliferation arrested senescent cell and possibly in an "aged" cell.
https://www.ulster.ac.uk/staff/t-rai
Additional affiliations
September 2008 - present
October 2008 - present
Publications
Publications (78)
Introduction: Cellular senescence is the irreversible growth arrest subsequent to oncogenic mutations, DNA damage, or metabolic insult. Senescence is associated with ageing and chronic age associated diseases such as cardiovascular disease and diabetes. The involvement of cellular senescence in acute kidney injury (AKI) and chronic kidney disease (...
Background: The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has posed unprecedented challenges to healthcare systems worldwide. Here, we have identified proteomic and genetic signatures for improved prognosis which is vital for COVID-19 research. Methods: We investigated the proteomic and genomic profile of COVID-19-positive pati...
Background: The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2 has posed unprecedented challenges to healthcare systems worldwide. Here, we have identified proteomic and genetic signatures for improved prognosis which is vital for COVID-19 research. Methods: We investigated the proteomic and genomic profile of COVID-19 positive patie...
Cellular senescence is the irreversible growth arrest subsequent to oncogenic mutations, DNA damage or metabolic insult. Senescence is associated with aging and chronic age associated diseases such as cardiovascular disease and diabetes. The involvement of cellular senescence in Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD) is not full...
Background
With the spread of SARS-CoV-2 impacting upon public health directly and socioeconomically, further information was required to inform policy decisions designed to limit virus spread during the pandemic. This study sought to contribute to serosurveillance work within Northern Ireland to track SARS-CoV-2 progression and guide health strate...
Background: With the impact of SARS-CoV-2 upon public health directly and socioeconomically, further information was required to inform policy decisions designed to limit virus spread. This study sought to contribute to serosurveillance work within Northern Ireland to track SARS-CoV-2 progression and guide health strategy.
Methods: Sera/plasma samp...
BACKGROUND
Background - Health organisations and countries around the world have found it difficult to control the spread of the coronavirus disease 2019. To minimise the impact on the NHS and improve patient care, there is a drive for rapid tests capable of detecting individuals who are at high risk of contracting severe COVID-19. Early work focus...
Background
Health organizations and countries around the world have found it difficult to control the spread of COVID-19. To minimize the future impact on the UK National Health Service and improve patient care, there is a pressing need to identify individuals who are at a higher risk of being hospitalized because of severe COVID-19. Early targeted...
Objective
The Covid Response Study (COVRES, NCT05548829) aims to carry out an integrated multi-omic analysis of factors contributing to host susceptibility to SARS-CoV-2 among a patient cohort of 1000 people from the geographically isolated island of Ireland.
Background
Health organisations and countries around the world have found it difficult to...
Severe COVID-19 is characterised by an overactive pro-inflammatory response of the immune system which is associated with new persistent symptoms. Differences in the persistence of symptoms, plasma inflammatory proteins and antibodies between hospitalised and non-hospitalised cases were investigated in the current study.
n=120 participants were rec...
We sought to determine the most efficacious and cost-effective strategy to follow when developing a national screening programme by comparing and contrasting the national screening programmes of Norway, the Netherlands and the UK. Comparing the detection rates and screening profiles between the Netherlands, Norway, the UK and constituent nations (E...
Aims. We sought to determine the most efficacious and cost effective strategy to follow when developing a national screening programme by comparing and contrasting the national screening programmes of Norway, the Netherlands and the UK.
Methods and results. Comparing the detection rates and screening profiles between the Netherlands, Norway, the UK...
Histone chaperone HIRA is thought to play a role in both early development and aging, but little is known about connections between the two processes. Here, we explore this relationship using a lineage-specific knockout mouse model, TyrCre::Hira fl/fl , in which HIRA is deficient in the pigmentary system consisting of embryonic melanoblasts, postna...
The current global pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has taken a substantial number of lives across the world. Although few vaccines have been rolled-out, a number of vaccine candidates are still under clinical trials at various pharmaceutical companies and laboratories around the world. Considering the in...
The dysregulated immune system represents a major target for improving health outcomes in a range of chronic conditions. This chapter describes key changes in the immune system as we age and showcases its dysregulation across five chronic conditions including diabetes, cardiovascular disease, and cancer, highlighting dysregulated key immune system...
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic associated with substantial morbidity and mortality worldwide, with particular risk for severe disease and mortality in the elderly population. SARS-CoV-2 infection is driven by a pathological hyperinflammat...
Vitamin D and cholesterol metabolism overlap significantly in the pathways that contribute to their biosynthesis. However, our understanding of their independent and co-regulation is limited. Cardiovascular disease is the leading cause of death globally and atherosclerosis, the pathology associated with elevated cholesterol, is the leading cause of...
Cellular senescence is a state of growth arrest that occurs after cells encounter various stresses. Senescence contributes to tumour suppression, embryonic development, and wound healing. It impacts on the pathology of various diseases by secreting inflammatory chemokines, immune modulators and other bioactive factors. These secretory biosignatures...
Systems medicine (SM) has emerged as a powerful tool for studying the human body at the systems level with the aim of improving our understanding, prevention and treatment of complex diseases. Being able to automatically extract relevant features needed for a given task from high-dimensional, heterogeneous data, deep learning (DL) holds great promi...
Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against her...
HIRA monoclonal antibody (mAb) validation.
HFt cells were stably transduced to express non-targeting control (shCtrl), Daxx- (shDaxx; secondary control), or HIRA- targeting (shHIRA; clones F2-F4) shRNAs. (A) Western blot analysis of the expression levels of HIRA (anti-HIRA mAb 04–1488, Millipore) in whole cell lysates derived from shCtrl, shDaxx, o...
HIRA is not recruited to PML-NBs in mock infected or uninfected cells on the periphery of a developing WT HSV-1 plaque.
Representative confocal microscopy images for quantitated data presented in Fig 2C. Wide-field images showing the nuclear localization of HIRA (red) and PML (cyan) in cells mock infected or in close proximity to a developing WT HS...
IFN-β induced HIRA localization at PML-NBs is cell-type dependent.
Representative confocal microscopy images for quantitated data presented in Fig 3G. Primary (MRC5, HFs, IMR-90), immortalized (MRC5t, HFt, RPE, HaCat), or carcinoma (U2OS, SAOS, HeLa, A549) cells were (A) mock treated or (B) stimulated with IFN-β (100 IU/ml) for 24 h (as indicated)....
HIRA depletion minimally effects ISG expression following IFN-β stimulation.
HFt cells were stably transduced to express non-targeting control (shCtrl) or HIRA -targeting (shHIRA) shRNAs. Cells were treated with IFN-β (100 IU/ml) for 9 or 17 h (as indicated). (A) qRT-PCR quantitation of Mx1, ISG54, ISG15, and OAS1 mRNA levels in IFN-β stimulated sh...
HIRA is recruited to PML-NBs in non-productively infected cells on the periphery of a developing ICP0-null mutant HSV-1 plaque.
Split channel confocal microscopy images for data presented in Fig 2A. Wide-field images showing the nuclear localization of HIRA (red) and PML (cyan) in cells in close proximity to a developing ICP0-null mutant HSV-1 plaq...
Inhibition of GSK-3α/β stimulates cell proliferation following release from cell cycle arrest.
HFt cells were seeded into 48-well plates and incubated in medium containing low serum (1% FBS) for 24 h to induce cell cycle arrest. Cells were released from starvation into medium containing high serum (10% FBS), 1 μM EdC, and either DMSO (carrier contr...
Pathway analysis of IFN-β stimulated or HSV-1 infected HFt shCtrl and shHIRA cells.
Reactome (https://reactome.org/) pathway analysis of high confidence transcriptome changes (FDR Q-value ≤ 0.0001, ≥ log2 fold change) identified following IFN-β (IFNb; 100 IU/ml) or HSV-1 (WT or ΔICP0 HSV-1, annotated WT and dICP0 HSV-1; MOI 1 PFU/cell) treatment of...
Differentially downregulated immune genes between IFN-β stimulated or HSV-1 infected HFt shCtrl and shHIRA cells.
Differential downregulated immune system genes identified by Reactome (https://reactome.org/) pathway analysis of treated (t) HFt shCtrl and shHIRA cells (as described in S4 Table). shHIRA (t)/shCtrl (t).
(XLSX)
Pathway analysis of untreated HFt shCtrl and shHIRA cells.
Reactome (https://reactome.org/) pathway analysis of high confidence transcriptome changes (FDR Q-value ≤ 0.0001, ≥ log2 fold change) identified between untreated (no treatment; nt) HFt shCtrl and shHIRA cells. shHIRA (nt)/shCtrl (nt).
(XLSX)
Pathway analysis of IFN-β stimulated or HSV-1 infected HFt shCtrl and shHIRA cells.
Reactome (https://reactome.org/) pathway analysis of high confidence transcriptome changes (FDR Q-value ≤ 0.0001, ≥ log2 fold change) identified following IFN-β (IFNb; 100 IU/ml) or HSV-1 (WT or ΔICP0 HSV-1, annotated WT and dICP0 HSV-1; MOI 1 PFU/cell) treatment of...
HIRA recruitment to PML-NBs in cells at the periphery of a developing ΔICP0 HSV-1 plaques is JAK-dependent.
Representative confocal microscopy images for quantitated data presented in Fig 2D. Wide-field images showing the nuclear localization of HIRA (red) and PML (cyan) in cells in close proximity to a developing ΔICP0 HSV-1 plaque-edge (eYFP.ICP4...
IFN-β induced HIRA localization at PML-NBs is Sp100 dependent.
(A, B) Representative confocal microscopy images for quantitated data presented in Fig 4D. HFt cells were stably transduced to express non-targeting control (shCtrl) or Sp100-targeting (shSp100) shRNAs. Cells were mock treated or stimulated with IFN-β (100 IU/ml) for 24 h (as indicated)...
ICP0 disrupts HIRA localization to input or nascent vDNA.
HFt cells were mock infected or infected with 3 PFU/cell of pre-labelled (HSV-1EdC or ΔICP0EdC) or pulse-labelled (0.5 μM EdC upon overlay) WT or ΔICP0 HSV-1 in the presence 50 μM acycloguanasine (ACG; to enable the visualization of input pre-labelled EdC viral genomes following the onset of...
Pathway analysis of IFN-β stimulated or HSV-1 infected HFt shCtrl cells.
Reactome (https://reactome.org/) pathway analysis of high confidence transcriptome changes (FDR Q-value ≤ 0.0001, ≥ log2 fold change) identified following IFN-β (IFNb; 100 IU/ml) or HSV-1 (WT or ΔICP0 HSV-1, annotated WT and dICP0 HSV-1; MOI 1 PFU/cell) treatment of HFt shCtrl...
Relative fold ISG transcriptome changes in HFt shCtrl and shHIRA cells following IFN-β stimulation or HSV-1 infection.
Relative fold ISG transcriptome [84] changes (FDR Q-value < 0.05) identified following IFN-β (IFNb; 100 IU/ml) or HSV-1 infection (WT or ΔICP0 HSV-1, annotated WT HSV1 and dICP0 HSV-1; MOI 1 PFU/cell) treatment. Conditions: shHIRA...
HIRA ChIP-seq alignment statistic and ISG enrichment analysis.
Mapped input control and HIRA ChIP-seq reads in untreated (neg.) or IFN-β treated (2000 IU/ml; Pos.) IMR-90 shCtrl and shPML cells (as indicated). Relative HIRA enrichment levels on 49 similarly sized interferon stimulated or non-interferon stimulated coding genes in mock (no treatment,...
The HIRA histone chaperone complex deposits histone H3.3 into nucleosomes in a DNA replication- and sequence-independent manner. As herpesvirus genomes enter the nucleus as naked DNA, we asked whether the HIRA chaperone complex affects herpesvirus infection. After infection of primary cells with HSV or CMV, or transient transfection with naked plas...
On acquisition of an oncogenic mutation, primary human and mouse cells can enter oncogene-induced senescence (OIS). OIS is characterized by a stable proliferation arrest and secretion of pro-inflammatory cytokines and chemokines, the senescence-associated secretory phenotype (SASP). Proliferation arrest and the SASP collaborate to enact tumor suppr...
Cellular senescence is a state of stable proliferation arrest of cells. The senescence pathway has many beneficial effects and is seen to be activated in damaged/stressed cells, as well as during embryonic development and wound healing. However, the persistence and accumulation of senescent cells in various tissues can also impair function and have...
Background
Histone modification H4K20me3 and its methyltransferase SUV420H2 have been implicated in suppression of tumorigenesis. The underlying mechanism is unclear, although H4K20me3 abundance increases during cellular senescence, a stable proliferation arrest and tumor suppressor process, triggered by diverse molecular cues, including activated...
Cellular senescence is a state of stable cell cycle arrest triggered by diverse stresses. Establishment of senescence occurs in conjunction with a multitude of chromatin changes, which are just beginning to be studied. These chromatin changes are hypothesized to be causative for senescence. Currently, a preferred method to study such changes is chr...
Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Pr...
Histone chaperones bind specific histones to mediate their storage, eviction or deposition from/or into chromatin. The HIRA histone chaperone complex, composed of HIRA, ubinuclein-1 (UBN1) and CABIN1, cooperates with the histone chaperone ASF1a to mediate H3.3-specific binding and chromatin deposition. Here we demonstrate that the conserved UBN1 Hp...
Cellular senescence is a stable proliferation arrest that suppresses tumorigenesis. Cellular senescence and associated tumor suppression depend on control of chromatin. Histone chaperone HIRA deposits variant histone H3.3 and histone H4 into chromatin in a DNA replication-independent manner. Appropriately for a DNA replication-independent chaperone...
Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation. Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease. The role of autophagy in cancer seems to be complex, with reports indi...
Altered DNA methylation and associated destabilization of genome integrity and function is a hallmark of cancer. Replicative senescence is a tumour suppressor process that imposes a limit on the proliferative potential of normal cells that all cancer cells must bypass. Here we show by whole-genome single-nucleotide bisulfite sequencing that replica...
Senescence is a stable proliferation arrest, associated with an altered secretory pathway, thought to promote tumor suppression and tissue aging. While chromatin regulation and lamin B1 down-regulation have been implicated as senescence effectors, functional interactions between them are poorly understood. We compared genome-wide Lys4 trimethylatio...
Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an auto...
The HIRA chaperone complex, comprised of HIRA, UBN1, and CABIN1, collaborates with histone-binding protein ASF1a to incorporate histone variant H3.3 into chromatin in a DNA replication-independent manner. To better understand HIRA's function and mechanism, we integrated HIRA, UBN1, ASF1a, and histone H3.3 chromatin immunoprecipitation sequencing an...
Concurrent activation of RAS/ERK and PI3K/AKT pathways is implicated in prostate cancer progression. The negative regulators of these pathways, including sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN), are commonly inactivated in prostate cancer. The molecular basis of cooperation between these genetic al...
The mammalian HIRA/UBN1/CABIN1/ASF1a (HUCA) histone chaperone complex deposits the histone H3 variant H3.3 into chromatin and is linked to gene activation, repression, and chromatin assembly in diverse cell contexts. We recently reported that a short N-terminal fragment of UBN1 containing amino acids 1-175 is necessary and sufficient for interactio...
Cellular senescence is an irreversible proliferation arrest, thought to contribute to tumor suppression, proper wound healing and, perhaps, tissue and organismal aging. Two classical tumor suppressors, p53 and pRB, control cell cycle arrest associated with senescence. Profound molecular changes occur in cells undergoing senescence. At the level of...
The mammalian HIRA/UBN1/ASF1a complex is a histone chaperone complex that is conserved from yeast (Saccharomyces cerevisiae) to humans. This complex preferentially deposits the histone variant H3.3 into chromatin in a DNA replication-independent
manner and is implicated in diverse chromatin regulatory events from gene activation to heterochromatini...
While the molecular basis of dilated cardiomyopathy (DCM) remains uncertain, concrete evidence is emerging that sarcomeric and cytoskeleton gene expression of myocardium isolated from failing versus non-failing patients differ dramatically. The central aim to this work was to find out the possible role of dystrophin and titin along with the TNF-alp...
Both idiopathic restrictive cardiomyopathy (IRCM) and hypertrophic cardiomyopathy (HCM) are part of the same disease spectrum and are due to sarcomeric gene mutations. A patient with restrictive physiology without left ventricular hypertrophy (LVH) would be diagnosed as IRCM, while one with LVH would be diagnosed as HCM with restrictive physiology....
Heart failure is a leading cause of mortality in South Asians. However, its genetic etiology remains largely unknown. Cardiomyopathies due to sarcomeric mutations are a major monogenic cause for heart failure (MIM600958). Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with her...
Inflammatory cytokine genes have been proposed as good candidate genes for conferring susceptibility to diabetic nephropathy. In the present study, we examined the combined effect of multiple alleles of pro inflammatory cytokine genes for determining the risk of nephropathy in type 2 diabetic patients.
Eight single nucleotide polymorphisms (SNPs) o...
Increased levels of TNF-alpha, IL-6, their soluble receptors, and NT-proBNP have been observed in patients with dilated cardiomyopathy (DCM). In the present study, we assessed the possible involvement of proinflammatory cytokines and their soluble receptors with and without recovery of LV function in DCM patients.
Forty patients with DCM were enrol...
Genetic predisposition has been proposed to be a major determinant in the development of renal complications of diabetes. Among candidate genes examined for susceptibility to diabetic nephropathy, angiotensin-converting enzyme (ACE) gene has been found to be associated with pathogenesis and progression of diabetic nephropathy. However, the role of...
The aim of the current study was to determine the frequency of mutations in the beta-myosin heavy chain gene (MYH7) in a cohort of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) and their families, and to investigate correlations between genotype and phenotype. About 130 consecutive patients diagnosed with HCM or DCM (69 with HC...
Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease, including diabetic nephropathy. Endothelial-derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with endothelial dysfunction. We evaluated the association of the constitutive endothelial nitric oxide synthase gene (...
Alterations in lipid metabolism and genetic predisposition are major risk factors for coronary artery disease (CAD). Variations in genes involved in lipid metabolism may act synergistically to confer risk or protection against CAD. The objective of the present study was to determine such interactions in variants of apolipoprotein E and apolipoprote...
The study was carried to determine the association of angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism with the risk of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM).
A total of 174 patients diagnosed with cardiomyopathy (118 with HCM, 51 with DCM, and 5 with RCM) and...
