A5077073440- Gut microbiota and health
- Genetics, Aging, and Longevity in Model Organisms
- Adipose Tissue and Metabolism
- Epigenetics and DNA Methylation
- Spaceflight effects on biology
- Immune Cell Function and Interaction
- Signaling Pathways in Disease
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Cellular transport and secretion
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Ion channel regulation and function
- Cell Adhesion Molecules Research
- Renal and related cancers
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Pluripotent Stem Cells Research
- Metabolism, Diabetes, and Cancer
- RNA modifications and cancer
- PI3K/AKT/mTOR signaling in cancer
- MicroRNA in disease regulation
- Immune Response and Inflammation
- Autophagy in Disease and Therapy
- NF-κB Signaling Pathways
- Circadian rhythm and melatonin
Babraham Institute
2016-2025
Imperial College London
2006
Hammersmith Hospital
2006
Autophagosome formation requires sequential translocation of autophagy-specific proteins to membranes enriched in PI3P and connected the ER. Preceding this, earliest structure forming de novo is a small punctum ULK1 complex. The provenance this its mode are unknown. We show that emerges from regions, where ATG9 vesicles align with ER exit coatomer function. Super-resolution microscopy reveals compartment consists regularly assembled punctate elements cluster progressively larger spherical...
Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At cellular level, ageing associated with reduced function, altered gene expression a perturbed epigenome. Recent work has demonstrated epigenome already rejuvenated by maturation phase of somatic cell reprogramming, which suggests full reprogramming not required reverse cells. Here we have developed first "maturation transient reprogramming" (MPTR) method, where factors are...
Cardiac hypertrophic growth in response to pathological cues is associated with reexpression of fetal genes and decreased cardiac function often a precursor heart failure. In contrast, physiologically induced hypertrophy adaptive, resulting improved function. The processes that selectively induce these states are poorly understood. Here, we have profiled 2 repressive epigenetic marks, H3K9me2 H3K27me3, which involved stable cellular differentiation, specifically cardiomyocytes from...
Since nuclear envelope breakdown occurs during mitosis in metazoan cells, it has been proposed that macroautophagy must be inhibited to maintain genome integrity. However, repression of remains controversial and mechanistic detail limited the suggestion CDK1 phosphorylates VPS34. Here, we show initiation macroautophagy, measured by translocation ULK complex autophagic puncta, is repressed mitosis, even when mTORC1 inhibited. Indeed, inactive reflecting its failure localize lysosomes due...
Inositol 1,4,5′-triphosphate receptor II (IP3RII) calcium channel expression is increased in both hypertrophic failing human myocardium and experimentally induced models of the disease. The ectopic released from these receptors induces pro-hypertrophic gene may promote arrhythmias. Here, we show that IP3RII was constitutively restrained by muscle-specific miRNA, miR-133a. During response to pressure overload or neurohormonal stimuli, miR-133a down-regulation permitted levels increase,...
Many membrane receptors activate phospholipase C (PLC) during signalling, triggering changes in the levels of several plasma (PM) lipids including PtdIns, PtdOH and PtdIns(4,5)P2. It is widely believed that exchange between PM endoplasmic reticulum (ER) required to restore lipid homeostasis PLC yet mechanism remains unresolved. RDGB a multi-domain protein with PITP domain (RDGB-PITPd). We find vitro, RDGB-PITPd binds transfers both PtdIns. In Drosophila photoreceptors experience high rates...
Normal function of the placenta depends on earliest developmental stages when trophoblast cells differentiate and invade into endometrium to establish definitive maternal-fetal interface. Previously, we identified ubiquitously expressed tumour suppressor BRCA1-associated protein 1 (BAP1) as a central factor novel molecular node controlling early mouse placentation. However, functional insights how BAP1 regulates biology are still missing. Using CRISPR/Cas9 knockout overexpression technology...
Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality widespread receptor expression, unexpected adverse events. Here, we developed novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs competitive fitness cost production among conventional CD4 T cells. CD8...
Abstract Heterochromatin maintains genome integrity and function, is organised into distinct nuclear domains. Some of these domains are proposed to form by phase separation through the accumulation HP1ɑ. Mouse heterochromatin contains noncoding major satellite repeats (MSR), which highly transcribed in mouse embryonic stem cells (ESCs). Here, we report that MSR transcripts can drive formation HP1ɑ droplets vitro, modulate dynamic condensates ESCs, contributing large characteristic...
Phosphatidic acid (PA) is postulated to have both structural and signaling functions during membrane dynamics in animal cells. In this study, we show that before a critical time period rhabdomere biogenesis Drosophila melanogaster photoreceptors, elevated levels of PA disrupt transport the apical domain. Lipidomic analysis shows effect associated with an increase abundance single, relatively minor molecular species PA. These defects are dependent on activation state Arf1. Transport via...
The germinal center (GC) response is critical for generating high-affinity humoral immunity and immunological memory, which forms the basis of successful immunization. Control GC thought to require follicular regulatory T (Tfr) cells, a subset suppressive Foxp3+ cells located within GCs. Relatively little known about exact role Tfr how they exert their function. A unique feature reported CXCR5-dependent localization GC. Here, we show that lack CXCR5 on results in reduced frequency, but not...
Upon DNA damage, the ALC1/CHD1L nucleosome remodeling enzyme (remodeler) is activated by binding to poly(ADP-ribose). How ALC1 recognizes nucleosome, as well how this recognition coupled remodeling, unknown. Here, we show that requires a wild-type acidic patch on entry side of nucleosome. The cryo-electron microscopy structure nucleosome-ALC1 linker complex reveals regulatory segment binds patch. Mutations within interface alter dynamics recruitment damage and impede ATPase activities ALC1....
Calcium phosphate (CaP) particle deposits are found in several inflammatory diseases including atherosclerosis and osteoarthritis. CaP, other forms of crystals particles, can promote inflammasome formation macrophages leading to caspase-1 activation secretion mature interleukin-1β (IL-1β). Given the close association small CaP particles with vascular smooth muscle cells (VSMCs) atherosclerotic fibrous caps, we aimed determine if affected pro-inflammatory signalling human VSMCs.
Inhibitor of kappa B (IκB) kinase β (IKKβ) has long been viewed as the dominant IKK in canonical nuclear factor-κB (NF-κB) signalling pathway, with IKKα being more important non-canonical NF-κB activation. Here we have investigated role and IKKβ activation colorectal cells using CRISPR-Cas9 knock-out cell lines, siRNA selective inhibitors. were redundant for IκBα phosphorylation turnover since loss or alone had little (SW620 cells) no (HCT116 effect. However, HCT116 was required basal p65 at...
Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play key role in coordinating the induction gene expression during hypertrophy. Induction immediate early (IEG) response including activator protein 1 (AP-1) complex factors necessary and event this process. How IEG are coupled hypertrophy not resolved. Here, vitro, rodent models human samples, we demonstrate MAPK-stimulated depends on mitogen stress-activated...
Clonal expansion of antigen-specific B-cells defines effective germinal centre responses and is key for the generation high-affinity antibodies. While positive selection in centres has been associated with anabolic metabolism cell growth, downstream drivers B-cell proliferation are not well understood. Here we report that RNA helicase DDX1 required maturation accrual dark-zone cellularity. Upon interaction T-follicular helper cells, DDX1-deficient upregulate c-MYC but do clonally expand. We...
Nlrp5 encodes a core component of the subcortical maternal complex (SCMC) cytoplasmic protein structure unique to mammalian oocyte and cleavage-stage embryo. NLRP5 mutations have been identified in patients presenting with early embryo arrest, recurrent molar pregnancies imprinting disorders. Correct patterning DNA methylation over imprinted domains during oogenesis is necessary for faithful genes. It was previously shown that oocytes mutation human SCMC gene KHDC3L had globally impaired...
Peptidylarginine deiminase IV (PADI4, PAD4) deregulation promotes the development of autoimmunity, cancer, atherosclerosis and age-related tissue fibrosis. PADI4 additionally mediates immune responses cellular reprogramming, although full extent its physiological roles is unexplored. Despite detailed molecular knowledge activation in vitro, we lack understanding regulation within cells, largely due to a appropriate systems tools. Here, develop apply set potent selective modulators. Using...
To survive elevated temperatures, ectotherms adjust the fluidity of membranes by fine-tuning lipid desaturation levels in a process previously described to be cell autonomous. We have discovered that, Caenorhabditis elegans, neuronal heat shock factor 1 (HSF-1), conserved master regulator response (HSR), causes extensive fat remodeling peripheral tissues. These changes include decrease desaturase and acid lipase expression intestine global shift saturation plasma membrane's phospholipids....
Despite considerable similarity in their amino acid sequences and structural features, the mammalian members of CLC chloride channel/transporter family have different subcellular locations. The location function one these members, hClC-4, is controversial. To characterize its cellular function, we investigated tissue distribution location. Expression was high excitable tissues such as nervous system skeletal muscle. When heterologously expressed HEK293 cells muscle fibers, hClC-4 localizes...
How intestinal epithelial cells interact with the microbiota and how this is regulated at gene expression level are critical questions. Smarcad1 a conserved chromatin remodeling factor poorly understood tissue function. As highly expressed in stem proliferative zones of epithelium, we explore its role tissue.Specific deletion mouse epithelium leads to colitis resistance substantial changes expression, including striking increase several genes linked innate immunity. Absence accessibility...