About
Tom is enabling people & organisations everywhere to deliver the impact that biology can…
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We are growing our London team! If you are an entrepreneurial investor or operator passionate about climate tech and backing exceptional founders…
We are growing our London team! If you are an entrepreneurial investor or operator passionate about climate tech and backing exceptional founders…
Liked by Tom Stubbs
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Fantastic announcement from Bayer | Consumer Health 👏 We are incredibly proud and excited about the partnership here with Bayer Consumer Health and…
Fantastic announcement from Bayer | Consumer Health 👏 We are incredibly proud and excited about the partnership here with Bayer Consumer Health and…
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I'm thrilled to see the cannabidiol (CBD) industry returning to its scientific roots. When we launched our pain-relieving CBD tampons in 2017, we…
I'm thrilled to see the cannabidiol (CBD) industry returning to its scientific roots. When we launched our pain-relieving CBD tampons in 2017, we…
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Experience
Education
Publications
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scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells.
Nature Communications
Parallel single-cell sequencing protocols represent powerful methods for investigating regulatory relationships, including epigenome-transcriptome interactions. Here, we report a single-cell method for parallel chromatin accessibility, DNA methylation and transcriptome profiling. scNMT-seq (single-cell nucleosome, methylation and transcription sequencing) uses a GpC methyltransferase to label open chromatin followed by bisulfite and RNA sequencing. We validate scNMT-seq by applying it to…
Parallel single-cell sequencing protocols represent powerful methods for investigating regulatory relationships, including epigenome-transcriptome interactions. Here, we report a single-cell method for parallel chromatin accessibility, DNA methylation and transcriptome profiling. scNMT-seq (single-cell nucleosome, methylation and transcription sequencing) uses a GpC methyltransferase to label open chromatin followed by bisulfite and RNA sequencing. We validate scNMT-seq by applying it to differentiating mouse embryonic stem cells, finding links between all three molecular layers and revealing dynamic coupling between epigenomic layers during differentiation.
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cuRRBS: simple and robust evaluation of enzyme combinations for reduced representation approaches.
Nucleic Acids Research
DNA methylation is an important epigenetic modification in many species that is critical for development, and implicated in ageing and many complex diseases, such as cancer. Many cost-effective genome-wide analyses of DNA modifications rely on restriction enzymes capable of digesting genomic DNA at defined sequence motifs. There are hundreds of restriction enzyme families but few are used to date, because no tool is available for the systematic evaluation of restriction enzyme combinations that…
DNA methylation is an important epigenetic modification in many species that is critical for development, and implicated in ageing and many complex diseases, such as cancer. Many cost-effective genome-wide analyses of DNA modifications rely on restriction enzymes capable of digesting genomic DNA at defined sequence motifs. There are hundreds of restriction enzyme families but few are used to date, because no tool is available for the systematic evaluation of restriction enzyme combinations that can enrich for certain sites of interest in a genome. Herein, we present customised Reduced Representation Bisulfite Sequencing (cuRRBS), a novel and easy-to-use computational method that solves this problem. By computing the optimal enzymatic digestions and size selection steps required, cuRRBS generalises the traditional MspI-based Reduced Representation Bisulfite Sequencing (RRBS) protocol to all restriction enzyme combinations. In addition, cuRRBS estimates the fold-reduction in sequencing costs and provides a robustness value for the personalised RRBS protocol, allowing users to tailor the protocol to their experimental needs. Moreover, we show in silico that cuRRBS-defined restriction enzymes consistently out-perform MspI digestion in many biological systems, considering both CpG and CHG contexts. Finally, we have validated the accuracy of cuRRBS predictions for single and double enzyme digestions using two independent experimental datasets.
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Multi-tissue DNA methylation age predictor in mouse
Genome Biology
Background
DNA methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this epigenetic clock is unique to humans or conserved in the more experimentally tractable mouse.
Results
We have generated a comprehensive set of genome-scale base-resolution methylation maps from…Background
DNA methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this epigenetic clock is unique to humans or conserved in the more experimentally tractable mouse.
Results
We have generated a comprehensive set of genome-scale base-resolution methylation maps from multiple mouse tissues spanning a wide range of ages. Many CpG sites show significant tissue-independent correlations with age which allowed us to develop a multi-tissue predictor of age in the mouse. Our model, which estimates age based on DNA methylation at 329 unique CpG sites, has a median absolute error of 3.33 weeks and has similar properties to the recently described human epigenetic clock. Using publicly available datasets, we find that the mouse clock is accurate enough to measure effects on biological age, including in the context of interventions. While females and males show no significant differences in predicted DNA methylation age, ovariectomy results in significant age acceleration in females. Furthermore, we identify significant differences in age-acceleration dependent on the lipid content of the diet.
Conclusions
Here we identify and characterise an epigenetic predictor of age in mice, the mouse epigenetic clock. This clock will be instrumental for understanding the biology of ageing and will allow modulation of its ticking rate and resetting the clock in vivo to study the impact on biological age. -
Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism
Genome Biology
Background
Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over…Background
Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time.
Results
Here, we profile genome-wide changes in DNA methylation, gene expression and lipidomics in response to DR and aging in female mouse liver. DR is generally strongly protective against age-related changes in DNA methylation. During aging with DR, DNA methylation becomes targeted to gene bodies and is associated with reduced gene expression, particularly of genes involved in lipid metabolism. The lipid profile of the livers of DR mice is correspondingly shifted towards lowered triglyceride content and shorter chain length of triglyceride-associated fatty acids, and these effects become more pronounced with age.
Conclusions
Our results indicate that DR remodels genome-wide patterns of DNA methylation so that age-related changes are profoundly delayed, while changes at loci involved in lipid metabolism affect gene expression and the resulting lipid profile. -
Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming
Cell Reports
Global DNA demethylation is an integral part of reprogramming processes in vivo and in vitro, but whether it occurs in the derivation of induced pluripotent stem cells (iPSCs) is not known. Here, we show that iPSC reprogramming involves both global and targeted demethylation, which are separable mechanistically and by their biological outcomes. Cells at intermediate-late stages of reprogramming undergo transient genome-wide demethylation, which is more pronounced in female cells. Global…
Global DNA demethylation is an integral part of reprogramming processes in vivo and in vitro, but whether it occurs in the derivation of induced pluripotent stem cells (iPSCs) is not known. Here, we show that iPSC reprogramming involves both global and targeted demethylation, which are separable mechanistically and by their biological outcomes. Cells at intermediate-late stages of reprogramming undergo transient genome-wide demethylation, which is more pronounced in female cells. Global demethylation requires activation-induced cytidine deaminase (AID)-mediated downregulation of UHRF1 protein, and abolishing demethylation leaves thousands of hypermethylated regions in the iPSC genome. Independently of AID and global demethylation, regulatory regions, particularly ESC enhancers and super-enhancers, are specifically targeted for hypomethylation in association with transcription of the pluripotency network. Our results show that global and targeted DNA demethylation are conserved and distinct reprogramming processes, presumably because of their respective roles in epigenetic memory erasure and in the establishment of cell identity.
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MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs
Cell Reports
Mouse embryonic stem cells are dynamic and heterogeneous. For example, rare cells cycle through a state characterized by decondensed chromatin and expression of transcripts, including the Zscan4 cluster and MERVL endogenous retrovirus, which are usually restricted to preimplantation embryos. Here, we further characterize the dynamics and consequences of this transient cell state. Single-cell transcriptomics identified the earliest upregulated transcripts as cells enter the MERVL/Zscan4 state…
Mouse embryonic stem cells are dynamic and heterogeneous. For example, rare cells cycle through a state characterized by decondensed chromatin and expression of transcripts, including the Zscan4 cluster and MERVL endogenous retrovirus, which are usually restricted to preimplantation embryos. Here, we further characterize the dynamics and consequences of this transient cell state. Single-cell transcriptomics identified the earliest upregulated transcripts as cells enter the MERVL/Zscan4 state. The MERVL/Zscan4 transcriptional network was also upregulated during induced pluripotent stem cell reprogramming. Genome-wide DNA methylation and chromatin analyses revealed global DNA hypomethylation accompanying increased chromatin accessibility. This transient DNA demethylation was driven by a loss of DNA methyltransferase proteins in the cells and occurred genome-wide. While methylation levels were restored once cells exit this state, genomic imprints remained hypomethylated, demonstrating a potential global and enduring influence of endogenous retroviral activation on the epigenome.
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The RNA-dependent RNA polymerase of the influenza A virus
Future Virology
The influenza A virus causes a highly contagious respiratory disease that significantly impacts our economy and health. Its replication and transcription is catalyzed by the viral RNA polymerase. This enzyme is also crucial for the virus, because it is involved in the adaptation of zoonotic strains. It is thus of major interest for the development of antiviral therapies and is being intensively studied. In this article, we will discuss recent advances that have improved our knowledge of the…
The influenza A virus causes a highly contagious respiratory disease that significantly impacts our economy and health. Its replication and transcription is catalyzed by the viral RNA polymerase. This enzyme is also crucial for the virus, because it is involved in the adaptation of zoonotic strains. It is thus of major interest for the development of antiviral therapies and is being intensively studied. In this article, we will discuss recent advances that have improved our knowledge of the structure of the RNA polymerase and how mutations in the polymerase help the virus to spread effectively among new hosts.
Other authors -
More activity by Tom
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August market the end of my time at Illumina. During these 9 years, I had the opportunity to contribute to an exciting technical roadmap and to drive…
August market the end of my time at Illumina. During these 9 years, I had the opportunity to contribute to an exciting technical roadmap and to drive…
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Hope for new insights into Endometriosis from cell mapping project! 🚨 A groundbreaking map of the human endometrium, the inner lining of the…
Hope for new insights into Endometriosis from cell mapping project! 🚨 A groundbreaking map of the human endometrium, the inner lining of the…
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We’re thrilled that our first funding call for Forecasting Tipping Points is now live. We’re looking to create an early warning system capable of…
We’re thrilled that our first funding call for Forecasting Tipping Points is now live. We’re looking to create an early warning system capable of…
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Anyone interested in the low abundant proteome measuring proteins down to a single femotgram per ml hit them up! They also have awesome mass spec…
Anyone interested in the low abundant proteome measuring proteins down to a single femotgram per ml hit them up! They also have awesome mass spec…
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Founder friends: Like many of you, the Snoots team is working hard at finding productivity gains in the amazing AI tools that are coming to the…
Founder friends: Like many of you, the Snoots team is working hard at finding productivity gains in the amazing AI tools that are coming to the…
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Farewell, Birmingham. It's been a blast! Let's see where the next adventure takes me...
Farewell, Birmingham. It's been a blast! Let's see where the next adventure takes me...
Liked by Tom Stubbs
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Introducing the yin to Ross Tomkins' yang, Ben Paglia. A man of many talents, Ben is also the Managing Director of the UKs first fully private…
Introducing the yin to Ross Tomkins' yang, Ben Paglia. A man of many talents, Ben is also the Managing Director of the UKs first fully private…
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🧬 Nutrigenetic DNA Test vs. Epigenetic Bio Age Test: What's the Difference? 🧬 When it comes to personalised health, understanding your body’s…
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Congratulations to Valentina Milanova 🇺🇦 and the team at Daye on this exciting and important work. Using a tampon as a collection device 🤯 In…
Congratulations to Valentina Milanova 🇺🇦 and the team at Daye on this exciting and important work. Using a tampon as a collection device 🤯 In…
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