W. Emmett

Using oligonucleotide signatures to build a system for effective detection of pathogenic bacteria in metagenomic samples

... Sarah for her love and interest in my work. Phillip Labuschagne and Werner Smidt for their ... more

Phage C2 Mediates Transduction of Tn6215, Encoding Erythromycin Resistance, between Clostridium difficile Strains

mBio, 2013

format_quotePhage C2 effectively mediates transfer of erm(B) resistance, with tens-of-millions PFU/ml utilized for successful transduction experiments.format_quote

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Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans

European Journal of Human Genetics, 2013

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DNA methylation analysis of murine hematopoietic side population cells during aging

Epigenetics, 2013

Stem cells have been found in most tissues/organs. These somatic stem cells produce replacements ... more Stem cells have been found in most tissues/organs. These somatic stem cells produce replacements for lost and damaged cells, and it is not completely understood how this regenerative capacity becomes diminished during aging. To study the possible involvement of epigenetic changes in somatic stem cell aging, we used murine hematopoiesis as a model system. Hematopoietic stem cells (HSCs) were enriched for via Hoechst exclusion activity (SP-HSC) from young, medium-aged and old mice and subjected to comprehensive, global methylome (MeDIP-seq) analysis. With age, we observed a global loss of DNA methylation of approximately 5%, but an increase in methylation at some CpG islands. Just over 100 significant (FDR&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.2) aging-specific differentially methylated regions (aDMRs) were identified, which are surprisingly few considering the profound age-based changes that occur in HSC biology. Interestingly, the polycomb repressive complex -2 (PCRC2) target genes Kiss1r, Nav2 and Hsf4 were hypermethylated with age. The promoter for the Sdpr gene was determined to be progressively hypomethylated with age. This occurred concurrently with an increase in gene expression with age. To explore this relationship further, we cultured isolated SP-HSC in the presence of 5-aza-deoxycytdine and demonstrated a negative correlation between Sdpr promoter methylation and gene expression. We report that DNA methylation patterns are well preserved during hematopoietic stem cell aging, confirm that PCRC2 targets are increasingly methylated with age, and suggest that SDPR expression changes with age in HSCs may be regulated via age-based alterations in DNA methylation.

The combination of transcriptomics and informatics identifies pathways targeted by miR-204 during neurogenesis and axon guidance

by J. Garcia-manteiga, Elia Stupka, W. Emmett, and Remo Sanges

Vertebrate organogenesis is critically sensitive to gene dosage and even subtle variations in the... more Vertebrate organogenesis is critically sensitive to gene dosage and even subtle variations in the expression levels of key genes may result in a variety of tissue anomalies. MicroRNAs (miRNAs) are fundamental regulators of gene expression and their role in vertebrate tissue patterning is just beginning to be elucidated. To gain further insight into this issue, we analysed the transcriptomic consequences of manipulating the expression of miR-204 in the Medaka fish model system. We used RNA-Seq and an innovative bioinformatics approach, which combines conventional differential expression analysis with the behavior expected by miR-204 targets after its overexpression and knockdown. With this approach combined with a correlative analysis of the putative targets, we identified a wider set of miR-204 target genes belonging to different pathways. Together, these approaches confirmed that miR-204 has a key role in eye development and further highlighted its putative function in neural differentiation processes, including axon guidance as supported by in vivo functional studies. Together, our results demonstrate the advantage of integrating next-generation sequencing and bioinformatics approaches to investigate miRNA biology and provide new important information on the role of miRNAs in the control of axon guidance and more broadly in nervous system development.

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Linguistic Approaches for Annotation, Visualization and Comparison of Prokaryotic Genomes and Environmental Sequences

by W. Emmett and Rian Pierneef

Systems and Computational Biology - Molecular and Cellular Experimental Systems, 2011

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Database tool ParkDB: a Parkinson’s disease gene expression database

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The combination of transcriptomics and informatics identifies pathways targeted by miR-204 during neurogenesis and axon guidance

by W. Emmett and Paola Bovolenta

Vertebrate organogenesis is critically sensitive to gene dosage and even subtle variations in the... more Vertebrate organogenesis is critically sensitive to gene dosage and even subtle variations in the expression levels of key genes may result in a variety of tissue anomalies. MicroRNAs (miRNAs) are fundamental regulators of gene expression and their role in vertebrate tissue patterning is just beginning to be elucidated. To gain further insight into this issue, we analysed the transcriptomic consequences of manipulating the expression of miR-204 in the Medaka fish model system. We used RNA-Seq and an innovative bioinformatics approach, which combines conventional differential expression analysis with the behavior expected by miR-204 targets after its overexpression and knockdown. With this approach combined with a correlative analysis of the putative targets, we identified a wider set of miR-204 target genes belonging to different pathways. Together, these approaches confirmed that miR-204 has a key role in eye development and further highlighted its putative function in neural differentiation processes, including axon guidance as supported by in vivo functional studies. Together, our results demonstrate the advantage of integrating next-generation sequencing and bioinformatics approaches to investigate miRNA biology and provide new important information on the role of miRNAs in the control of axon guidance and more broadly in nervous system development.

format_quoteDifferential expression analysis revealed strong enrichment of genes in pathways like nervous system development (adj. P-value = 4.8 × 10 -28), notably 'axon guidance'.format_quote

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Fine-Mapping, Gene Expression and Splicing Analysis of the Disease Associated LRRK2 Locus

PLoS ONE, 2013

Association studies have identified several signals at the LRRK2 locus for Parkinson's disease (P... more Association studies have identified several signals at the LRRK2 locus for Parkinson's disease (PD), Crohn's disease (CD) and leprosy. However, little is known about the molecular mechanisms mediating these effects. To further characterize this locus, we fine-mapped the risk association in 5,802 PD and 5,556 controls using a dense genotyping array (ImmunoChip). Using samples from 134 post-mortem control adult human brains (UK Human Brain Expression Consortium), where up to ten brain regions were available per individual, we studied the regional variation, splicing and regulation of LRRK2. We found convincing evidence for a common variant PD association located outside of the LRRK2 protein coding region (rs117762348, A.G, P = 2.56610 28 , case/control MAF 0.083/0.074, odds ratio 0.86 for the minor allele with 95% confidence interval [0.80-0.91]). We show that mRNA expression levels are highest in cortical regions and lowest in cerebellum. We find an exon quantitative trait locus (QTL) in brain samples that localizes to exons 32-33 and investigate the molecular basis of this eQTL using RNA-Seq data in n = 8 brain samples. The genotype underlying this eQTL is in strong linkage disequilibrium with the CD associated non-synonymous SNP rs3761863 (M2397T). We found two additional QTLs in liver and monocyte samples but none of these explained the common variant PD association at rs117762348. Our results characterize the LRRK2 locus, and highlight the importance and difficulties of fine-mapping and integration of multiple datasets to delineate pathogenic variants and thus develop an understanding of disease mechanisms. Citation: Trabzuni D, Ryten M, Emmett W, Ramasamy A, Lackner KJ, et al. (2013) Fine-Mapping, Gene Expression and Splicing Analysis of the Disease Associated LRRK2 Locus. PLoS ONE 8(8): e70724.

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ParkDB: a Parkinson's disease gene expression database

Database, 2011

format_quoteParkDB compiles thorough microarray data from multiple sources, enhancing uniformity in gene expression analysis across diverse experiments.format_quote

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UCbase 2.0: ultraconserved sequences database (2014 update)

by Riccardo Martoglia, Federica Mandreoli, Vincenzo Lomonaco, W. Emmett, and Silvio Bicciato

Database, 2014

Citation details: Lomonaco,V., Martoglia,R., Mandreoli,F. et al. UCbase 2.0: ultraconserved seque... more

format_quoteDespite the majority of UCRs lacking known functions, a few are implicated in transcriptional enhancement and alternative splicing mechanisms.format_quote

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