ORCID Profile
0000-0001-9763-703X
Current Organisation
Nanyang Technological University
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Publisher: Wiley
Date: 04-2009
DOI: 10.1111/J.1749-6632.2008.03823.X
Abstract: Derived from fibroblasts, myofibroblasts are the principal cells that are responsible for the synthesis and reorganization of excess matrix in renal interstitial fibrosis. Recognized from their de novo expression of alpha-smooth muscle actin, myofibroblast differentiation and activity can be influenced by several factors, including a combination of growth factors and other soluble mediators, extracellular matrix components, and mechanical stress. Relaxin has previously been shown to inhibit renal myofibroblast differentiation in vitro, an effect partly mediated through its ability to interfere with the transforming growth factor-beta1 (TGF-beta1) pathway via inhibition of Smad2 phosphorylation and translocation. Furthermore, endogenous relaxin has been shown to protect the kidney from a myofibroblast-mediated model of injury in vivo. However, the pathways involved in the interaction between relaxin and TGF-beta1 remain unknown. In this report, the inhibitory actions of relaxin on TGF-beta1-induced renal myofibroblast differentiation are summarized to date, and the potential signaling pathways that are implicated in relaxin's inhibitory actions are discussed.
Publisher: Oxford University Press (OUP)
Date: 10-12-2016
DOI: 10.1111/BJD.14767
Publisher: Wiley
Date: 11-02-2022
DOI: 10.1111/EXD.14536
Abstract: Androgenetic alopecia (AGA) is a prevalent hair loss condition in males that develops due to the influence of androgens and genetic predisposition. With the aim of elucidating genes involved in AGA pathogenesis, we modelled AGA with three‐dimensional culture of keratinocyte‐surrounded dermal papilla (DP) cells. We co‐cultured immortalised balding and non‐balding human DP cells (DPCs) derived from male AGA patients with epidermal keratinocyte (NHEK) using multi‐interfacial polyelectrolyte complexation technique. We observed up‐regulated mitochondria‐related gene expression in balding compared with non‐balding DP aggregates which indicated altered mitochondria metabolism. Further observation of significantly reduced electron transport chain complex activity (complexes I, IV and V), ATP levels and ability to uptake metabolites for ATP generation demonstrated compromised mitochondria function in balding DPC. Balding DP was also found to be under significantly higher oxidative stress than non‐balding DP. Our experiments suggest that application of antioxidants lowers oxidative stress levels and improves metabolite uptake in balding DPC. We postulate that the observed up‐regulation of mitochondria‐related genes in balding DP aggregates resulted from an over‐compensatory effort to rescue decreased mitochondrial function in balding DP through the attempted production of new functional mitochondria. In all, our three‐dimensional co‐culturing revealed mitochondrial dysfunction in balding DPC, suggesting a metabolic component in the aetiology of AGA.
Publisher: Hindawi Limited
Date: 08-2014
DOI: 10.1002/HUMU.22636
Abstract: MED13L is a component subunit of the Mediator complex, an important regulator of transcription that is highly conserved across eukaryotes. Here, we report MED13L disruption in a translocation t(12 ) breakpoint of a patient with Pierre-Robin syndrome, moderate intellectual disability, craniofacial anomalies, and muscular defects. The phenotype is similar to previously described patients with MED13L haploinsufficiency. Knockdown of MED13L orthologue in zebrafish, med13b, showed early defective migration of cranial neural crest cells (NCCs) that contributed to cartilage structure deformities in the later stage, recapitulating craniofacial anomalies seen in human patients. Notably, we observed abnormal distribution of developing neurons in different brain regions of med13b morphant embryos, which could be rescued upon introduction of full-length human MED13L mRNA. To compare with mammalian system, we suppressed MED13L expression by short-hairpin RNA in ES-derived human neural progenitors, and differentiated them into neurons. Transcriptome analysis revealed differential expression of components of Wnt and FGF signaling pathways in MED13L-deficient neurons. Our finding provides a novel insight into the mechanism of overlapping phenotypic outcome targeting NCCs derivatives organs in patients with MED13L haploinsufficiency, and emphasizes a clinically recognizable syndromic phenotype in these patients.
Publisher: Oxford University Press (OUP)
Date: 11-2017
DOI: 10.1111/BJD.15807
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.JID.2016.03.032
Abstract: Androgenetic alopecia (AGA) is a common heritable and androgen-dependent hair loss condition in men. Twelve genetic risk loci are known to date, but it is unclear which genes at these loci are relevant for AGA. Dermal papilla cells (DPCs) located in the hair bulb are the main site of androgen activity in the hair follicle. Widely used monolayer-cultured primary DPCs in hair-related studies often lack dermal papilla characteristics. In contrast, immortalized DPCs have high resemblance to intact dermal papilla. We derived immortalized human DPC lines from balding (BAB) and non-balding (BAN) scalp. Both BAB and BAN retained high proportions of dermal papilla signature gene and versican protein expression. We performed expression analysis of BAB and BAN and annotated AGA risk loci with differentially expressed genes. We found evidence for AR but not EDA2R as the candidate gene at the AGA risk locus on chromosome X. Further, our data suggest TWIST1 (twist family basic helix-loop-helix transcription factor 1) and SSPN (sarcospan) to be the functionally relevant AGA genes at the 7p21.1 and 12p12.1 risk loci, respectively. Down-regulated genes in BAB compared to BAN were highly enriched for vasculature-related genes, suggesting that deficiency of DPC from balding scalps in fostering vascularization around the hair follicle may contribute to the development of AGA.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.NEUROBIOLAGING.2018.09.013
Abstract: Recent whole-exome sequencing studies in European patients with Parkinson's disease (PD) have identified potential risk variants across 33 novel PD candidate genes. We aim to determine if these reported candidate genes are similarly implicated in Asians by assessing common, rare, and novel nonsynonymous coding variants by sequencing all 33 genes in 198 Chinese s les and genotyping coding variants in an independent set of 9756 Chinese s les. We carried out further targeted sequencing of CD36 in an additional 576 Chinese and Korean s les. We found that only 8 of 43 reported risk variants were polymorphic in our Chinese s les. We identified several heterozygotes for rare loss-of-function mutations, including the reported CD36 p.Gln74Ter variant, in both cases and controls. We also observed 2 potential compound heterozygotes among PD cases for rare loss-of-function mutations in CD36 and SSPO. The other reported variants were common in East Asians and not associated with PD, completely absent, or only found in controls. Therefore, the 33 reported candidate genes and associated variants are unlikely to confer significant PD risk in the East Asian population.
Publisher: Public Library of Science (PLoS)
Date: 06-03-2014
Publisher: Public Library of Science (PLoS)
Date: 22-08-2012
Publisher: Springer Science and Business Media LLC
Date: 08-03-2017
DOI: 10.1038/NCOMMS14694
Abstract: Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci ( P × 10 −8 , METAL) of which 23 have not been reported previously. The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes ( FGF5 , IRF4 , DKK2 ) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for the development of novel therapeutic options. The data provide molecular evidence that rather than being an isolated trait, MPB shares a substantial biological basis with numerous other human phenotypes and may deserve evaluation as an early prognostic marker, for ex le, for prostate cancer, sudden cardiac arrest and neurodegenerative disorders.
Publisher: Springer Science and Business Media LLC
Date: 19-06-2011
DOI: 10.1038/NG.857
Publisher: Springer Science and Business Media LLC
Date: 27-07-2011
DOI: 10.1038/NG0811-815A
Publisher: Proceedings of the National Academy of Sciences
Date: 07-03-2022
Abstract: With obesity on the rise, there is a growing appreciation for intracellular lipid droplet (LD) regulation. Here, we show how saturated fatty acids (SFAs) reduce fat storage–inducing transmembrane protein 2 (FIT2)–facilitated, pancreatic β cell LD biogenesis, which in turn induces β cell dysfunction and death, leading to diabetes. This mechanism involves direct acylation of FIT2 cysteine residues, which then marks the FIT2 protein for endoplasmic reticulum (ER)–associated degradation. Loss of β cell FIT2 and LDs reduces insulin secretion, increases intracellular ceramides, stimulates ER stress, and exacerbates diet-induced diabetes in mice. While palmitate and stearate degrade FIT2, unsaturated fatty acids such as palmitoleate and oleate do not, results of which extend to nutrition and diabetes.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.CELREP.2015.06.020
Abstract: Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H(+) leakage, and the fusion might contribute to invasiveness once a cell is transformed.
No related grants have been discovered for Elaine Chew.