A5102715689- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- DNA Repair Mechanisms
- Coastal wetland ecosystem dynamics
- Cancer Cells and Metastasis
- RNA modifications and cancer
- Single-cell and spatial transcriptomics
- Legume Nitrogen Fixing Symbiosis
- Pluripotent Stem Cells Research
- RNA and protein synthesis mechanisms
- CRISPR and Genetic Engineering
- PARP inhibition in cancer therapy
- Cancer-related molecular mechanisms research
- Cancer-related gene regulation
- Digestive system and related health
- Microtubule and mitosis dynamics
- Genetics and Neurodevelopmental Disorders
- Cell death mechanisms and regulation
- MicroRNA in disease regulation
- Chromatin Remodeling and Cancer
- Mitochondrial Function and Pathology
- Protist diversity and phylogeny
- Gene Regulatory Network Analysis
- Cancer-related Molecular Pathways
University of Central Florida
2011-2025
University of Dundee
2017-2024
MRC Protein Phosphorylation and Ubiquitylation Unit
2020-2024
Wellcome Trust
2023-2024
Rockefeller University
2023
Imperial College London
2013-2021
MRC London Institute of Medical Sciences
2017-2021
The University of Melbourne
2017-2019
Hammersmith Hospital
2015-2017
IBM Research - Australia
2017
Senescence is a stress-responsive form of stable cell cycle exit. Senescent cells have distinct gene expression profile, which often accompanied by the spatial redistribution heterochromatin into senescence-associated heterochromatic foci (SAHFs). Studying key component nuclear lamina lamin B1 (LMNB1), we report dynamic alterations in its genomic profile and their implications for SAHF formation regulation during senescence. Genome-wide mapping reveals that LMNB1 depleted senescence,...
BackgroundSeizure prediction can increase independence and allow preventative treatment for patients with epilepsy. We present a proof-of-concept seizure system that is accurate, fully automated, patient-specific, tunable to an individual's needs.MethodsIntracranial electroencephalography (iEEG) data of ten obtained from advisory were analyzed as part pseudoprospective study. First, deep learning classifier was trained distinguish between preictal interictal signals. Second, performance...
Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) potential therapeutic target. Here, we describe RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses differentially affects other components. Among candidates was PTBP1. PTBP1 regulates alternative splicing...
In addition to mediating sister chromatid cohesion during the cell cycle, cohesin complex associates with CTCF and active gene regulatory elements form long-range interactions between its binding sites. Genome-wide chromosome conformation capture had shown that cohesin's main role in interphase genome organization is within architectural compartments, rather than specifying compartments per se. However, it remains unclear how cohesin-mediated contribute regulation of expression. We have...
Abstract Branched ubiquitin (Ub) chains constitute a sizable fraction of Ub polymers in human cells. Despite their abundance, our understanding branched function cell signaling has been stunted by the absence accessible methods and tools. Here we identify cellular branched-chain-specific binding proteins devise approaches to probe K48–K63-branched function. We establish method monitor cleavage linkages within complex unveil ATXN3 MINDY as debranching enzymes. engineer K48–K63 branch-specific...
The discovery of cytosine hydroxymethylation (5hmC) as a mechanism that potentially controls DNA methylation changes typical neoplasia prompted us to investigate its behaviour in colon cancer. 5hmC is globally reduced proliferating cells such tumours and the gut crypt progenitors, from which can arise. Here, we show colorectal cancer express Ten-Eleven-Translocation (TET) transcripts at levels similar normal tissues. Genome-wide analyses promoters marked by tissue, those identified TET2...
T cell receptor (TCR) signals can elicit full activation with acquisition of effector functions or a state anergy. Here, we ask whether microRNAs affect the interpretation TCR signaling. We find that Dicer-deficient CD4 cells fail to correctly discriminate between activating and anergy-inducing stimuli produce IL-2 in absence co-stimulation. Excess production by was sufficient override anergy induction WT restore inducible Foxp3 expression Il2-deficient cells. Phosphorylation Akt on S473 S6...
Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem (iPSCs). Reprogramming is a slow inefficient process, suggesting presence safeguarding mechanisms that counteract cell fate conversion. One such mechanism senescence. To identify modulators reprogramming-induced senescence, we performed genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In screen, identified novel mediators OSKM-induced...
Salt-inducible kinase 2 (SIK2) is a multifunctional of the AMPK family that plays role in CREB1-mediated gene transcription and was recently reported to have therapeutic potential ovarian cancer. The expression this investigated prostate cancer clinical specimens. Interestingly, auto-antibodies against SIK2 were increased plasma patients with aggressive disease. Examination cells found it functions both as positive regulator cell-cycle progression negative CREB1 activity. Knockdown inhibited...
During late mitosis and the early G1 phase, origins of replication are licensed by binding to double hexamers MCM2–7. In this study, we investigated how licensing proliferative commitment coupled in epithelium small intestine. We developed a method for identifying cells intact tissue containing DNA-bound Interphase above transit-amplifying compartment had no MCM2–7, but still expressed MCM2–7 protein, suggesting that is inhibited immediately upon differentiation. Strikingly, found most Lgr5+...
Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS induce liver tumors. controls p16INK4a p21CIP1a transcription but also regulates DNA damage, oxidative stress, p53 induction, suggesting that uses additional mechanisms regulate senescence....
Mouse embryonic stem (ES) cells are a popular model system to study biological processes, though uncovering recessive phenotypes requires inactivating both alleles. Building upon resources from the International Knockout Consortium (IKMC), we developed targeting vector for second allele inactivation in conditional-ready IKMC 'knockout-first' ES cell lines. We applied our technology several epigenetic regulators, recovering bi-allelic targeted clones with high efficiency of 60% and used Flp...
The NEK1 kinase controls ciliogenesis, mitosis, and DNA repair, mutations cause human diseases including axial spondylometaphyseal dysplasia amyotrophic lateral sclerosis. C21ORF2 a similar pattern of diseases, suggesting close functional links with . Here, we report that endogenous form tight complex in cells. A interaction domain “CID” at the C-terminus is necessary for its association cells, pathogenic this region disrupt complex. AlphaFold modelling predicts an extended binding interface...
Jarid2 is part of the Polycomb Repressor complex 2 (PRC2) responsible for genome-wide H3K27me3 deposition. Unlike other PRC2-deficient embryonic stem cells (ESCs), however, Jarid2-deficient ESCs show a severe differentiation block, altered colony morphology, and distinctive patterns deregulated gene expression. Here, we that Jarid2−/− express constitutively high levels Nanog but reduced PCP signaling components Wnt9a, Prickle1, Fzd2 lowered β-catenin activity. Depletion Wnt9a/Prickle1/Fzd2...
Turning genes on and off is essential for development homeostasis, yet little known about the sequence causal role of chromatin state changes during repression active genes. This surprising, as defective gene silencing underlies developmental abnormalities disease. Here we delineate functional contribution transcriptional mechanisms at high temporal resolution. Inducible entry NuRD-interacting regulator Ikaros into mouse pre-B cell nuclei triggered immediate binding to target promoters....
Cohesin is implicated in establishing and maintaining pluripotency. Whether this because of essential cohesin functions the cell cycle or gene regulation unknown. Here we tested cohesin's contribution to reprogramming systems that reactivate expression pluripotency genes absence proliferation (embryonic stem [ES] heterokaryons) DNA replication (nuclear transfer). Contrary expectations, depletion enhanced ability ES cells initiate somatic heterokaryons. This was explained by increased c-Myc...
Mutations in the gene encoding CDKL5 kinase are among most common genetic causes of childhood epilepsy and can also give rise to severe neurodevelopmental condition CDD (CDKL5 deficiency disorder). Despite its importance for human health, phosphorylation targets cellular roles poorly understood, especially cell nucleus. Here, we report that is recruited sites DNA damage actively transcribed regions A quantitative phosphoproteomic screen nuclear substrates reveals a network transcriptional...
Abstract Multi-omics approaches use a diversity of high-throughput technologies to profile the different molecular layers living cells. Ideally, integration this information should result in comprehensive systems models cellular physiology and regulation. However, most multi-omics projects still include limited number assays there have been very few multi-omic studies that evaluate dynamic processes such as growth, development adaptation. Hence, we lack formal analysis methods datasets can...
Homeostasis of renewing tissues requires balanced proliferation, differentiation and movement. This is particularly important in the intestinal epithelium where lineage tracing suggests that stochastic choices are intricately coupled to position a cell relative niche. To determine how achieved, we followed proliferating cells organoids discovered behaviour mitotic sisters predicted long-term positioning. We found that, normally, 70% remain neighbours, while 30% lose contact separate after...
Abstract More than 90% of colorectal cancers carry mutations in Apc that drive tumourigenesis. A 'just-right' signalling model proposes stimulate optimal, but not excessive Wnt signalling, resulting a growth advantage mutant over wild-type cells. Reversal this constitutes potential therapeutic approach. We utilised intestinal organoids to compare the and Organoids derived from Min/+ mice recapitulate stages polyposis culture. They eventually form spherical cysts reflect competitive cells...