A5004512950- Mass Spectrometry Techniques and Applications
- Advanced Proteomics Techniques and Applications
- Epigenetics and DNA Methylation
- Protein Degradation and Inhibitors
- Cancer-related gene regulation
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- Metabolomics and Mass Spectrometry Studies
- Genomics and Phylogenetic Studies
- Analytical Chemistry and Chromatography
- CRISPR and Genetic Engineering
- Pluripotent Stem Cells Research
- RNA and protein synthesis mechanisms
- Bacterial Genetics and Biotechnology
- Cutaneous Melanoma Detection and Management
- Acute Myeloid Leukemia Research
- Cancer Research and Treatments
- Ion-surface interactions and analysis
- Cancer Genomics and Diagnostics
- Genetic Syndromes and Imprinting
- Genetics and Neurodevelopmental Disorders
- Microbial Natural Products and Biosynthesis
- Melanoma and MAPK Pathways
- Pancreatic function and diabetes
- Liver Disease Diagnosis and Treatment
Imperial College London
2023-2025
MRC London Institute of Medical Sciences
2024
Medical Research Council
2024
Memorial Sloan Kettering Cancer Center
2019-2023
University of Southern Denmark
2016-2023
University of Cambridge
2013-2016
University of Edinburgh
2011
Abstract Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and has been proposed to regulate transcription initiation 1,2 . However, redundant functions the H3K4 SET1/COMPASS methyltransferase complexes complicate elucidation specific role H3K4me3 in regulation 3,4 Here, using mouse embryonic stem cells as a model system, we show that acute ablation shared subunits leads complete loss all methylation. Turnover occurs more rapidly than H3K4me1...
Histone proteins bind DNA and organize the genomes of eukaryotes most archaea, whereas bacteria rely on different nucleoid-associated proteins. Homology searches have detected putative histone-fold domains in a few bacteria, but whether these function like archaeal/eukaryotic histones is unknown. Here we report that are major chromatin components Bdellovibrio bacteriovorus Leptospira interrogans. Patterns sequence evolution suggest important roles for additional bacterial clades. Crystal...
qTOF mass spectrometry and traveling wave ion mobility separation (TWIMS) hybrid instruments (q-TWIMS-TOF) have recently become commercially available. Ion allows an additional dimension of precursor inside the instrument, without incurring increase in instrument time. We comprehensively investigated effects TWIMS on data-independent acquisition a Synapt G2 instrument. observed that if fragmentation is performed post TWIMS, more accurate assignment fragment ions to precursors possible data...
Label-free quantitation by data independent methods (for instance MS(E)) is growing in popularity due to the high technical reproducibility of mass spectrometry analysis. The recent introduction Synapt hybrid instruments capable incorporating ion mobility separation within analysis now allows acquisition definition MS(E) (HDMS(E)). HDMS(E) enables deeper proteome coverage and more confident peptide identifications when compared MS(E), while latter offers a higher dynamic range for...
Comprehensive characterization of proteomes comprising the same proteins with distinct post-translational modifications (PTMs) is a staggering challenge. Many such proteoforms are isomers (localization variants) that require separation followed by top-down or middle-down mass spectrometric analyses, but condensed-phase separations ineffective in those size ranges. The variants for "middle-down" peptides were resolved differential ion mobility spectrometry (FAIMS), relying on increment at...
Abstract Aims/hypothesis Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of make distinct contributions to overall control insulin secretion. These include subpopulation highly connected ‘hub’ cells, important for propagation intercellular Ca 2+ waves. Functional subpopulations have also been demonstrated in human beta with an altered subtype distribution apparent type 2 diabetes. At present, molecular mechanisms through which cell...
The proteomic composition of the Arabidopsis (Arabidopsis thaliana) Golgi apparatus is currently reasonably well documented; however, little known about relative abundances between different proteins within this compartment. Accurate quantitative information resident great importance: it facilitates a better understanding biochemical processes that take place organelle, especially those polysaccharide synthesis pathways. are challenging to quantify because abundance organelle relatively low...
Histone proteins are subject to dynamic post-translational modifications (PTMs) that cooperatively modulate the chromatin structure and function. Nearly all functional PTMs found on N-terminal histone domains (tails) of ∼50 residues protruding from nucleosome core. Using high-definition differential ion mobility spectrometry (FAIMS) with electron transfer dissociation, we demonstrate rapid baseline gas-phase separation identification tails involving monomethylation, trimethylation,...
Epigenetic regulators are frequently mutated in hematological malignancies including acute myeloid leukemia (AML). Thus, the identification and characterization of novel epigenetic drivers affecting AML biology holds potential to improve our basic understanding uncover options for therapeutic intervention. To identify tumor suppressive AML, we performed an vivo short hairpin RNA (shRNA) screen context CEBPA mutant AML. This identified Histone 3 Lysine 4 (H3K4) demethylase KDM5C as a...
Abstract Severe alcohol-related hepatitis (sAH) is a life-threatening form of liver disease (ARLD) associated with significant short-term mortality. Opportunistic infections due to impaired immune function are major cause patient Mitochondrial dysfunction within the well-recognised feature ARLD and sAH. However, whether these hepatic mitochondrial defects extend system sAH patients, underlying their dysfunction, remains unclear. Here, we demonstrate that monocytes exhibit an increased...
Abstract Diet is believed to be an important mediator of oncogenesis and response anti-cancer therapies, although no evidence-based dietary guidelines exist for patients with cancer. Limiting protein intake can suppress tumor growth by both inducing nutrient stress enhancing anti-tumor immunity. However, little known about the impact reducing on efficacy chemotherapy, most widely used treatment. Here, we present evidence that in mice 50% stops established tumors, parallel a DNA damage....
Bacteria of the genus Streptomyces are a model system for bacterial multicellularity. Their mycelial life style involves formation long multinucleated hyphae during vegetative growth, with occasional cross-walls separating compartments. Reproduction occurs by specialized aerial hyphae, which differentiate into chains uninucleoid spores. While tubulin-like FtsZ protein is required all peptidoglycan-based septa in Streptomyces, canonical divisome-dependent cell division only sporulation. Here...
Understanding the molecular underpinnings of pluripotency is a prerequisite for optimal maintenance and application embryonic stem cells (ESCs). While protein-protein interactions core factors have been identified in mouse ESCs, their interactome human ESCs (hESCs) has not to date explored. Here we mapped OCT4 interactomes naïve primed hESCs, revealing extensive connections mammalian ATP-dependent nucleosome remodeling complexes. In associated with both BRG1 BRM, two paralog ATPases BAF...
Intact protein sequencing by tandem mass spectrometry (MS/MS), known as top-down sequencing, relies on efficient gas-phase fragmentation at multiple experimental conditions to achieve extensive amino acid sequence coverage. We developed the "topdownr" R-package for automated construction of multimodal (i.e., involving CID, HCD, ETD, ETciD, EThcD, and UVPD) MS/MS methods an orbitrap instrument platform systematic analysis resultant spectra. used topdownr generate analyze thousands spectra...
Streptomycetes are multicellular bacteria with complex developmental cycles. They of biotechnological importance as they produce most bioactive compounds used in biomedicine,
Strong orthogonality to mass spectrometry makes differential ion mobility (FAIMS) a powerful tool for isomer separations. However, high FAIMS resolution has been achieved overall only with buffers rich in He or H2. That obstructed coupling Fourier transform spectrometers operating under ultrahigh vacuum, but exceptional m/z and accuracy of FTMS are indispensable frontline biological environmental applications. By raising the waveform amplitude 6 kV, we enabled using solely N2 thus...
Biological functions of many proteins are governed by post-translational modifications (PTMs). In particular, the rich PTM complement in histones controls gene expression and chromatin structure with major health implications via a combinatoric language. Deciphering that "histone code" is great challenge for proteomics given an astounding number possible proteoforms, including isomers different positions. These must be disentangled on top- or middle-down level to preserve key connectivity,...