A5021463132- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- RNA Research and Splicing
- Liver Disease Diagnosis and Treatment
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Liver physiology and pathology
- Genomics and Phylogenetic Studies
- Neonatal Respiratory Health Research
- Occupational and environmental lung diseases
- Cytokine Signaling Pathways and Interactions
- Endoplasmic Reticulum Stress and Disease
- Machine Learning in Bioinformatics
- Genomics and Rare Diseases
- IL-33, ST2, and ILC Pathways
- Cardiac Fibrosis and Remodeling
- Chronic Kidney Disease and Diabetes
- Cancer-related molecular mechanisms research
- Drug-Induced Hepatotoxicity and Protection
- Immune Cell Function and Interaction
- Diabetes Treatment and Management
- Genetic Associations and Epidemiology
- Peptidase Inhibition and Analysis
- Renal Diseases and Glomerulopathies
- Adipose Tissue and Metabolism
- Genetics, Aging, and Longevity in Model Organisms
Duke-NUS Medical School
2017-2025
National University of Singapore
2017-2024
Agency for Science, Technology and Research
2020
Genome Institute of Singapore
2017-2020
Indian Institute of Technology Madras
2015-2016
Philips (United States)
2015
Philips (Finland)
2013
Case Comprehensive Cancer Center
2013
Yale Cancer Center
2013
University Hospitals Seidman Cancer Center
2013
Interleukin-11 is important for lung fibroblast activation in idiopathic pulmonary fibrosis, and its signaling represents a therapeutic target.
We studied the role of interleukin 11 (IL11) signaling in pathogenesis nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models NASH.We stimulated human fibroblasts, HSCs, or hepatocytes with IL11 other cytokines analyzed them by imaging, immunoblot, functional assays enzyme-linked immunosorbent assays. Mice were given injections IL11. disruption receptor subunit alpha1 gene (Il11ra1-/-) mice Il11ra1+/+ fed a high-fat methionine-...
For healthspan and lifespan, ERK, AMPK mTORC1 represent critical pathways inflammation is a centrally important hallmark
Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show new upstream start codons, and disrupting stop sites existing uORFs, under strong negative selection. This selection signal is significantly stronger for arising genes intolerant to loss-of-function variants. Furthermore, creating...
Abstract Ribosome profiling quantifies the genome‐wide ribosome occupancy of transcripts. With integration matched RNA sequencing data, translation efficiency (TE) genes can be calculated to reveal translational regulation. This layer gene‐expression regulation is otherwise difficult assess on a global scale and generally not well understood in context human disease. Current statistical methods calculate differences TE have low accuracy, cannot accommodate complex experimental designs or...
Fibrosis is a common pathology in many cardiac disorders and driven by the activation of resident fibroblasts. The global posttranscriptional mechanisms underlying fibroblast-to-myofibroblast conversion heart have not been explored.Genome-wide changes RNA transcription translation during human fibroblast were monitored with sequencing ribosome profiling. We then used RNA-binding protein-based analyses to identify translational regulators fibrogenic genes. integration occupancy levels 30...
Abstract IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma liver disease unclear. Here, we investigate of hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete response to lipid loading. Autocrine activity causes death through NOX4-derived ROS, activation ERK, JNK caspase-3, impaired mitochondrial function reduced fatty acid oxidation. Paracrine stimulates hepatic stellate cells fibrosis. In mouse models NASH,...
Mito-SEPs are small open reading frame-encoded peptides that localize to the mitochondria regulate metabolism. Motivated by an intriguing negative association between mito-SEPs and inflammation, here we screen for modify inflammatory outcomes report a mito-SEP named "Modulator of cytochrome C oxidase during Inflammation" (MOCCI) is upregulated inflammation infection promote host-protective resolution. MOCCI, paralog NDUFA4 subunit (Complex IV), replaces in Complex IV lower mitochondrial...
Inhibition of IL11 signaling limits drug-induced liver damage and promotes hepatic regeneration in a mouse model.
Interleukin 11 (IL11) is upregulated in inflammatory conditions, where it mostly believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 promotes inflammation by activating fibroblasts. Here, we assessed whether pro- or Primary cultures of human kidney, lung skin fibroblasts were stimulated with resulted the transient phosphorylation signal transducer and activator transcription 3 (STAT3) sustained activation extracellular signal-regulated protein...
The kidney has large regenerative capacity, but this is compromised when damage excessive and renal tubular epithelial cells (TECs) undergo SNAI1-driven growth arrest. Here we investigate the role of IL11 in TECs, injury repair. stimulation TECs induces ERK- p90RSK-mediated GSK3β inactivation, SNAI1 upregulation pro-inflammatory gene expression. Mice with acute upregulate leading to expression dysfunction, which not seen Il11 deleted mice or administered a neutralizing antibody either...
Abstract Background Untranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length UTRs and the composition regulatory elements within them known to vary substantially across genes, but little is about reasons for this variation in humans. Here, we set out determine whether variation, specifically 5’UTRs, correlates with gene dosage sensitivity. Results We investigate 5’UTR length, number alternative transcription start sites, potential splicing, type...
Repetitive pulmonary injury causes fibrosis and inflammation that underlies chronic lung diseases such as idiopathic (IPF). Interleukin 11 (IL11) is important for fibroblast activation but the contribution of fibroblast-specific IL11 activity to fibro-inflammation not known. To address this gap in knowledge, we generated mice with loxP-flanked Il11ra1 deleted receptor adult fibroblasts (CKO mice). In bleomycin (BLM) model fibrosis, CKO had reduced lesser ERK activation, diminished immune...
Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 mechanistically linked activation of human dermal (HDFs) SSc or controls.We measured serum levels volunteers early diffuse manipulated signalling HDFs using gain- loss-of-function approaches that combined molecular cellular phenotyping.In SSc, are elevated as compared healthy controls. All transforming growth factor beta (TGFβ) isoforms induced...
A major scientific drive is to characterize the protein-coding genome as it provides primary basis for study of human health. But fundamental question remains: what has been missed in prior genomic analyses? Over past decade, translation non-canonical open reading frames (ncORFs) observed across cell types and disease states, with implications proteomics, genomics, clinical science. However, impact ncORFs limited by absence a large-scale understanding their contribution proteome. Here, we...
Abstract Loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and incompletely penetrant craniosynostosis. The impact LOF has not been characterized. We generated knockout ( Il11 −/− ) mice that are born expected ratios have normal hematological profiles. Lung fibroblasts from resistant to pro-fibrotic stimulation with TGFβ1. Following bleomycin-induced lung injury, protected pulmonary fibrosis exhibit lesser ERK, STAT3 NF-kB activation,...
Titin-truncating variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy. TTNtv occur in ~1% general population and causes subclinical cardiac remodeling asymptomatic carriers. In rat models with either proximal or distal TTNtv, we previously showed altered metabolism at baseline impaired function response to stress. However, molecular mechanism(s) underlying these effects remains unknown. current study, used investigate effect on autophagy mitochondrial function, which...
Abstract Summary To enable direct comparison of ancestry background in different studies, we developed LASER to estimate individual by placing either sezquenced or genotyped samples a common space, regardless the sequencing strategy genotyping array used characterize each sample. Here describe server facilitate application method wide range genetic studies. The provides estimation for geographic regions and user-friendly interactive visualization results. Availability Implementation is...
The tumor suppressor LKB1/STK11 plays important roles in regulating cellular metabolism and stress responses its mutations are associated with various cancers. We recently identified a novel exon 1b within intron 1 of human LKB1/STK11, which generates an alternatively spliced, mitochondria-targeting LKB1 isoform for mitochondrial oxidative stress. Here we examined the formation this uncovered relatively late emergence during evolution. Analyses putative genomic sequences primate superfamily...
Abstract Thousands of short open reading frames (sORFs) are translated outside annotated coding sequences. Recent studies have pioneered searching for sORF-encoded microproteins in mass spectrometry (MS)-based proteomics and peptidomics datasets. Here, we assessed literature-reported MS-based identifications unannotated human proteins. We find that vary by three orders magnitude the number proteins they report. Of nearly 10,000 reported peptides, 96% were unique to a single study, 12% mapped...
The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade promotes cardiomyocyte hypertrophy and is cardioprotective, with the three RAF kinases forming a node for signal integration. Our aims were to determine if BRAF relevant human heart failure, whether hypertrophy, Type 1 inhibitors developed cancer (that paradoxically activate ERK1/2 at low concentrations: 'RAF paradox') may have same effect. was up-regulated in samples from patients failure compared normal controls. We assessed...