A5077629876- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- RNA Research and Splicing
- Acute Myeloid Leukemia Research
- Hematopoietic Stem Cell Transplantation
- Immune Cell Function and Interaction
- Cancer, Hypoxia, and Metabolism
- Zebrafish Biomedical Research Applications
- RNA modifications and cancer
- Amino Acid Enzymes and Metabolism
- Prostate Cancer Treatment and Research
- Hemoglobinopathies and Related Disorders
- Viral Infections and Vectors
- Erythrocyte Function and Pathophysiology
- Cancer-related molecular mechanisms research
- Pancreatic function and diabetes
- Iron Metabolism and Disorders
- Telomeres, Telomerase, and Senescence
- Reproductive Biology and Fertility
- Immune cells in cancer
- IL-33, ST2, and ILC Pathways
- Genetics, Aging, and Longevity in Model Organisms
- Osteoarthritis Treatment and Mechanisms
- Blood disorders and treatments
- Cancer-related gene regulation
Medical Research Council
2008-2022
University of Oxford
2008-2022
MRC Weatherall Institute of Molecular Medicine
2011-2022
John Radcliffe Hospital
2017-2022
Institute of Molecular Medicine
2008
Genes on different chromosomes can be spatially associated in the nucleus several transcriptional and regulatory situations; however, functional significance of such associations remains unclear. Using human erythropoiesis as a model, we show that five cotranscribed genes, which are found four chromosomes, associate with each other at significant but variable frequencies. Those genes most frequently association lie decondensed stretches chromatin. By replacing mouse α-globin gene cluster...
Significance The hypoxic microenvironment in solid tumors is known to reduce the efficacy of anticancer treatments many cancer types, including breast cancer. This study shows hypoxia induces an amino acid transporter, SNAT2, which then causes resistance antihormone therapy. We show major interplay between genes induced by estrogen receptor and hypoxia. Hypoxia-inducible factor 1α compensates for loss expression receptor-α (ERα) maintaining SNAT2 under or endocrine therapies. overexpression...
Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response inhibitory drugs, yet its role in nucleus poorly characterized. Here, we investigated significance cancers and cell line models. In prostate cancers, was predominantly membrane localized benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic)...
Hepcidin regulates systemic iron homeostasis. Suppression of hepcidin expression occurs physiologically in deficiency and increased erythropoiesis but is pathologic thalassemia hemochromatosis. Here we show that epigenetic events govern expression. Erythropoiesis suppress via erythroferrone-dependent -independent mechanisms, respectively, vivo, both involve reversible loss H3K9ac H3K4me3 at the locus. In vitro, pan-histone deacetylase inhibition elevates expression, vivo maintains...
Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream mouse hematopoietic stem cells (HSCs), FLT3 internal tandem duplications (FLT3 ITDs) have recently been to intrinsically suppress HSCs. Herein, single-cell interrogation found Flt3 mRNA be absent in large majority phenotypic HSCs, with a strong negative correlation between and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers an even more severe loss...
Plasmacytoid dendritic cells (pDCs) produce type I interferon (IFN-I) and are traditionally defined as being BDCA-2+CD123+. pDCs not readily detectable in healthy human skin, but have been suggested to accumulate wounds. Here, we describe a CD1a-bearing BDCA-2+CD123int DC subset that rapidly infiltrates skin wounds comprises major population. Using single-cell RNA sequencing, show these largely activated DCs acquiring features compatible with lymph node homing antigen presentation,...
The Zika virus (ZIKV) has received much attention due to an alarming increase in cases of neurological disorders including congenital syndrome associated with infection. To date, there is no effective treatment available. An immediate response by the innate immune system crucial for control virus. Using CRISPR/Cas9-mediated knockouts A549 cells, we investigated individual contributions RIG-I-like receptors MDA5 and RIG-I ZIKV sensing this using a Brazilian strain. We show that main sensor...
Abstract Mast cell products and high levels of type 2 cytokines are associated with severe dengue disease. Group innate lymphoid cells (ILC2) type-2 cytokine-producing that activated by epithelial mast cell-derived lipid mediators. Through ex vivo RNAseq analysis, we observed ILC2 during acute viral infection, show an impaired I-IFN signature in We circulating permissive for virus infection vitro, particularly when through prostaglandin D (PGD ). underwent productive which was inhibited...
During development, it is unclear if lineage-fated cells derive from multilineage-primed progenitors and whether active mechanisms operate to restrict cell fate. Here we investigate how mesoderm specifies into blood-fated cells. We document temporally restricted co-expression of blood (Scl/Tal1), cardiac (Mesp1) paraxial (Tbx6) lineage-affiliated transcription factors in single cells, at the onset specification, supporting existence common progenitors. At same time-restricted stage, absence...
Somatic mutations in acute myeloid leukemia are acquired sequentially and hierarchically. First, pre-leukemic mutations, such as t(8;21) that encodes AML1-ETO, within the hematopoietic stem cell (HSC) compartment, while signaling pathway including KRAS activating late events during transformation of leukemic progenitor cells rarely detectable HSC. This raises possibility detrimental to clonal expansion To address this hypothesis, we used conditional genetics introduce Aml1-ETO K-RasG12D into...
Abstract Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α (ERα) positive breast cancer. Hypoxia known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here we show that the glutamine transporter, SNAT2, AA transporter most frequently induced cancer it regulated HIF1α both in-vitro in-vivo xenografts. SNAT2 induction MCF7 cells was also ERα but became predominantly a HIF-1α-dependent gene under hypoxia. Relevant this,...
Mitochondrial quality is implicated as a contributor to declining fertility with aging. We investigated mitochondrial transcripts in oocytes and their associated cumulus cells from mice of different ages using RNA-seq. Mice aged 3 weeks, 9 1 year were superovulated, 48 h later, oocyte complexes collected by follicle puncture. did not detect any major differences that could be attributed However, RNA which deviated the consensus sequence found at higher frequency than corresponding oocyte....
<div>Abstract<p>Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response inhibitory drugs, yet its role in nucleus poorly characterized. Here, we investigated significance cancers and cell line models. In prostate cancers, was predominantly membrane localized benign glands, while malignant epithelium contained prominent...
<p>Supplementary file containing: Supplementary methods Table S1: Primers, probes and siRNAs used in this study. S2: Demographics of men treated by radical prostatectomy for prostate cancer. S3: IGF-1R scores clinical parameters undergoing localized S4: ChIP-seq: mapped reads. Figure Characterization expression subcellular localization ChIP-seq human cancer cells containing nuclear IGF-1R. identifies binding peaks promoters JUN FAM21 but not CCDN1 or IGF1R. Investigating functional...
<p>Supplementary file containing: Supplementary methods Table S1: Primers, probes and siRNAs used in this study. S2: Demographics of men treated by radical prostatectomy for prostate cancer. S3: IGF-1R scores clinical parameters undergoing localized S4: ChIP-seq: mapped reads. Figure Characterization expression subcellular localization ChIP-seq human cancer cells containing nuclear IGF-1R. identifies binding peaks promoters JUN FAM21 but not CCDN1 or IGF1R. Investigating functional...
<div>Abstract<p>Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response inhibitory drugs, yet its role in nucleus poorly characterized. Here, we investigated significance cancers and cell line models. In prostate cancers, was predominantly membrane localized benign glands, while malignant epithelium contained prominent...