ORCID Profile
0000-0002-4390-0872
Current Organisations
University of Southampton
,
Duke-NUS Graduate Medical School
,
Duke-NUS
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In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Medical Biotechnology | Logistics and Supply Chain Management | Biomaterials | Regenerative Medicine (incl. Stem Cells and Tissue Engineering) |
Human Pharmaceutical Products not elsewhere classified | Expanding Knowledge in the Medical and Health Sciences | Technological and Organisational Innovation
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.CELREP.2017.11.029
Abstract: Our current understanding of induced pluripotent stem cell (iPSC) generation has almost entirely been shaped by studies performed on reprogramming fibroblasts. However, whether the resulting model universally applies to the reprogramming process of other cell types is still largely unknown. By characterizing and profiling the reprogramming pathways of fibroblasts, neutrophils, and keratinocytes, we unveil that key events of the process, including loss of original cell identity, mesenchymal to epithelial transition, the extent of developmental reversion, and reactivation of the pluripotency network, are to a large degree cell-type specific. Thus, we reveal limitations for the use of fibroblasts as a universal model for the study of the reprogramming process and provide crucial insights about iPSC generation from alternative cell sources.
Publisher: Springer Science and Business Media LLC
Date: 03-2014
DOI: 10.1038/NATURE12787
Publisher: Wiley
Date: 17-08-2019
DOI: 10.1002/ACN3.50850
Publisher: Public Library of Science (PLoS)
Date: 25-03-2015
Publisher: Springer Science and Business Media LLC
Date: 13-11-2017
DOI: 10.1038/NATURE24676
Publisher: Springer Science and Business Media LLC
Date: 25-11-2019
DOI: 10.1038/S41593-019-0539-4
Abstract: There is currently little information available about how in idual cell types contribute to Alzheimer's disease. Here we applied single-nucleus RNA sequencing to entorhinal cortex s les from control and Alzheimer's disease brains (n = 6 per group), yielding a total of 13,214 high-quality nuclei. We detail cell-type-specific gene expression patterns, unveiling how transcriptional changes in specific cell subpopulations are associated with Alzheimer's disease. We report that the Alzheimer's disease risk gene APOE is specifically repressed in Alzheimer's disease oligodendrocyte progenitor cells and astrocyte subpopulations and upregulated in an Alzheimer's disease-specific microglial subopulation. Integrating transcription factor regulatory modules with Alzheimer's disease risk loci revealed drivers of cell-type-specific state transitions towards Alzheimer's disease. For ex le, transcription factor EB, a master regulator of lysosomal function, regulates multiple disease genes in a specific Alzheimer's disease astrocyte subpopulation. These results provide insights into the coordinated control of Alzheimer's disease risk genes and their cell-type-specific contribution to disease susceptibility. These results are available at adsn.ddnetbio.com.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2023
DOI: 10.1038/S41586-023-06424-7
Abstract: Cells undergo a major epigenome reconfiguration when reprogrammed to human induced pluripotent stem cells (hiPS cells). However, the epigenomes of hiPS cells and human embryonic stem (hES) cells differ significantly, which affects hiPS cell function 1–8 . These differences include epigenetic memory and aberrations that emerge during reprogramming, for which the mechanisms remain unknown. Here we characterized the persistence and emergence of these epigenetic differences by performing genome-wide DNA methylation profiling throughout primed and naive reprogramming of human somatic cells to hiPS cells. We found that reprogramming-induced epigenetic aberrations emerge midway through primed reprogramming, whereas DNA demethylation begins early in naive reprogramming. Using this knowledge, we developed a transient-naive-treatment (TNT) reprogramming strategy that emulates the embryonic epigenetic reset. We show that the epigenetic memory in hiPS cells is concentrated in cell of origin-dependent repressive chromatin marked by H3K9me3, lamin-B1 and aberrant CpH methylation. TNT reprogramming reconfigures these domains to a hES cell-like state and does not disrupt genomic imprinting. Using an isogenic system, we demonstrate that TNT reprogramming can correct the transposable element overexpression and differential gene expression seen in conventional hiPS cells, and that TNT-reprogrammed hiPS and hES cells show similar differentiation efficiencies. Moreover, TNT reprogramming enhances the differentiation of hiPS cells derived from multiple cell types. Thus, TNT reprogramming corrects epigenetic memory and aberrations, producing hiPS cells that are molecularly and functionally more similar to hES cells than conventional hiPS cells. We foresee TNT reprogramming becoming a new standard for biomedical and therapeutic applications and providing a novel system for studying epigenetic memory.
Publisher: Cold Spring Harbor Laboratory
Date: 17-05-2019
DOI: 10.1101/639054
Abstract: The important role of microglia, the brain’s resident immune cells, in Alzheimer’s disease (AD) is now well recognized, however their molecular and functional ersity and underlying mechanisms still remain controversial. To transcriptionally and functionally characterize the ersity of microglia in AD and aging, we isolated the amyloid plaque-containing (XO4 + ) and non-containing (XO4 − ) microglia from an AD mouse model. Transcriptomics analysis unveiled independent transcriptional trajectories in ageing and AD. XO4 + microglial transcriptomes linked plaque phagocytosis to altered expression of bona fide late onset AD genetic risk factors. We further revealed that the XO4 + transcriptional program is present in a subset of human microglia from AD patients and is a direct and reversible consequence of Aβ plaque phagocytosis. Conversely, XO4 − microglia in AD displayed an accelerated ageing signature and contained more intracellular post synaptic material than plaque-containing microglia, despite reduced active synaptosome phagocytosis. Mechanistically, we predicted HIF1α as a core regulator of the XO4 − /XO4 + axis, and further validated the mechanism in vitro using human stem cell-derived microglia like cells and primary human microglia. Together these findings unveiled the molecular mechanism underpinning the functional ersity of microglia in AD, providing opportunities to develop treatments targeted at subset specific manipulation of the microglial niche.
Publisher: Elsevier BV
Date: 2021
Publisher: Cold Spring Harbor Laboratory
Date: 07-2020
Abstract: Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2 .
Publisher: American Chemical Society (ACS)
Date: 24-02-2021
Publisher: Proceedings of the National Academy of Sciences
Date: 27-03-2014
Abstract: Naturally occurring regulatory T (Treg) cells, which specifically express the transcription factor forkhead box P3 (Foxp3), are engaged in the maintenance of immunological self-tolerance and homeostasis. By transcriptional start site cluster analysis, we assessed here how genome-wide patterns of DNA methylation or Foxp3 binding sites were associated with Treg-specific gene expression. We found that Treg-specific DNA hypomethylated regions were closely associated with Treg up-regulated transcriptional start site clusters, whereas Foxp3 binding regions had no significant correlation with either up- or down-regulated clusters in nonactivated Treg cells. However, in activated Treg cells, Foxp3 binding regions showed a strong correlation with down-regulated clusters. In accordance with these findings, the above two features of activation-dependent gene regulation in Treg cells tend to occur at different locations in the genome. The results collectively indicate that Treg-specific DNA hypomethylation is instrumental in gene up-regulation in steady state Treg cells, whereas Foxp3 down-regulates the expression of its target genes in activated Treg cells. Thus, the two events seem to play distinct but complementary roles in Treg-specific gene expression.
Publisher: Cold Spring Harbor Laboratory
Date: 14-05-2019
DOI: 10.1101/628347
Abstract: Alzheimer’s disease (AD) is a heterogeneous disease that is largely dependent on the complex cellular microenvironment in the brain. This complexity impedes our understanding of how in idual cell types contribute to disease progression and outcome. To characterize the molecular and functional cell ersity in the human AD brain we utilized single nuclei RNA- seq in AD and control patient brains in order to map the landscape of cellular heterogeneity in AD. We detail gene expression changes at the level of cells and cell subclusters, highlighting specific cellular contributions to global gene expression patterns between control and Alzheimer’s patient brains. We observed distinct cellular regulation of APOE which was repressed in oligodendrocyte progenitor cells (OPCs) and astrocyte AD subclusters, and highly enriched in a microglial AD subcluster. In addition, oligodendrocyte and microglia AD subclusters show discordant expression of APOE. Integration of transcription factor regulatory modules with downstream GWAS gene targets revealed subcluster-specific control of AD cell fate transitions. For ex le, this analysis uncovered that astrocyte ersity in AD was under the control of transcription factor EB (TFEB), a master regulator of lysosomal function and which initiated a regulatory cascade containing multiple AD GWAS genes. These results establish functional links between specific cellular sub-populations in AD, and provide new insights into the coordinated control of AD GWAS genes and their cell-type specific contribution to disease susceptibility. Finally, we created an interactive reference web resource which will facilitate brain and AD researchers to explore the molecular architecture of subtype and AD-specific cell identity, molecular and functional ersity at the single cell level. We generated the first human single cell transcriptome in AD patient brains Our study unveiled 9 clusters of cell-type specific and common gene expression patterns between control and AD brains, including clusters of genes that present properties of different cell types (i.e. astrocytes and oligodendrocytes) Our analyses also uncovered functionally specialized sub-cellular clusters: 5 microglial clusters, 8 astrocyte clusters, 6 neuronal clusters, 6 oligodendrocyte clusters, 4 OPC and 2 endothelial clusters, each enriched for specific ontological gene categories Our analyses found manifold AD GWAS genes specifically associated with one cell-type, and sets of AD GWAS genes co-ordinately and differentially regulated between different brain cell-types in AD sub-cellular clusters We mapped the regulatory landscape driving transcriptional changes in AD brain, and identified transcription factor networks which we predict to control cell fate transitions between control and AD sub-cellular clusters Finally, we provide an interactive web-resource that allows the user to further visualise and interrogate our dataset. Data resource web interface : adsn.ddnetbio.com
Publisher: Springer Science and Business Media LLC
Date: 21-05-2021
DOI: 10.1038/S41467-021-23111-1
Abstract: The role of microglia cells in Alzheimer’s disease (AD) is well recognized, however their molecular and functional ersity 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 in iduals 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 ersity of microglia in AD.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2020
DOI: 10.1038/S41586-020-2734-6
Abstract: The reprogramming of human somatic cells to primed or naive induced pluripotent stem cells recapitulates the stages of early embryonic development
Publisher: Informa UK Limited
Date: 11-2016
Publisher: Oxford University Press (OUP)
Date: 27-10-2016
DOI: 10.1093/NAR/GKW995
Publisher: Springer Science and Business Media LLC
Date: 03-2017
DOI: 10.1038/NATURE21374
Publisher: Springer Science and Business Media LLC
Date: 03-2014
DOI: 10.1038/NATURE13182
Publisher: Elsevier BV
Date: 2021
Publisher: Springer Science and Business Media LLC
Date: 14-01-2015
DOI: 10.1038/NCOMMS7066
Abstract: In evolution, body plan complexity increases due to an increase in the number of in idualized cell types. Yet, there is very little understanding of the mechanisms that produce this form of organismal complexity. One model for the origin of novel cell types is the sister cell-type model. According to this model, each cell type arises together with a sister cell type through specialization from an ancestral cell type. A key prediction of the sister cell-type model is that gene expression profiles of cell types exhibit tree structure. Here we present a statistical model for detecting tree structure in transcriptomic data and apply it to transcriptomes from ENCODE and FANTOM5. We show that transcriptomes of normal cells harbour substantial amounts of hierarchical structure. In contrast, cancer cell lines have less tree structure, suggesting that the emergence of cancer cells follows different principles from that of evolutionary cell-type origination.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2016
DOI: 10.1038/NG.3487
Abstract: Transdifferentiation, the process of converting from one cell type to another without going through a pluripotent state, has great promise for regenerative medicine. The identification of key transcription factors for reprogramming is currently limited by the cost of exhaustive experimental testing of plausible sets of factors, an approach that is inefficient and unscalable. Here we present a predictive system (Mogrify) that combines gene expression data with regulatory network information to predict the reprogramming factors necessary to induce cell conversion. We have applied Mogrify to 173 human cell types and 134 tissues, defining an atlas of cellular reprogramming. Mogrify correctly predicts the transcription factors used in known transdifferentiations. Furthermore, we validated two new transdifferentiations predicted by Mogrify. We provide a practical and efficient mechanism for systematically implementing novel cell conversions, facilitating the generalization of reprogramming of human cells. Predictions are made available to help rapidly further the field of cell conversion.
Publisher: Springer Science and Business Media LLC
Date: 09-04-2021
DOI: 10.1038/S41467-021-22397-5
Abstract: Mito-SEPs are small open reading frame-encoded peptides that localize to the mitochondria to regulate metabolism. Motivated by an intriguing negative association between mito-SEPs and inflammation, here we screen for mito-SEPs that modify inflammatory outcomes and report a mito-SEP named “Modulator of cytochrome C oxidase during Inflammation” (MOCCI) that is upregulated during inflammation and infection to promote host-protective resolution. MOCCI, a paralog of the NDUFA4 subunit of cytochrome C oxidase (Complex IV), replaces NDUFA4 in Complex IV during inflammation to lower mitochondrial membrane potential and reduce ROS production, leading to cyto-protection and d ened immune response. The MOCCI transcript also generates miR-147b, which targets the NDUFA4 mRNA with similar immune d ening effects as MOCCI, but simultaneously enhances RIG-I/MDA-5-mediated viral immunity. Our work uncovers a dual-component pleiotropic regulation of host inflammation and immunity by MOCCI (C15ORF48) for safeguarding the host during infection and inflammation.
Publisher: Springer Science and Business Media LLC
Date: 17-03-2021
Publisher: Springer Science and Business Media LLC
Date: 27-05-2020
DOI: 10.1038/S41467-019-10717-9
Abstract: Upstream open reading frames (uORFs) are tissue-specific cis -regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes.
Publisher: Oxford University Press (OUP)
Date: 29-03-2014
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 01-2021
End Date: 11-2027
Amount: $4,969,663.00
Funder: Australian Research Council
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