Nicki Gray
University of Oxford
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Publication
Featured researches published by Nicki Gray.
Journal of Cell Biology | 2008
Jill M. Brown; Joanne Green; Ricardo Pires das Neves; Helen Wallace; Andrew Smith; Jim R. Hughes; Nicki Gray; Steve Taylor; William G. Wood; Douglas R. Higgs; Francisco J. Iborra; Veronica J. Buckle
Genes on different chromosomes can be spatially associated in the nucleus in several transcriptional and regulatory situations; however, the functional significance of such associations remains unclear. Using human erythropoiesis as a model, we show that five cotranscribed genes, which are found on four different chromosomes, associate with each other at significant but variable frequencies. Those genes most frequently in association lie in decondensed stretches of chromatin. By replacing the mouse α-globin gene cluster in situ with its human counterpart, we demonstrate a direct effect of the regional chromatin environment on the frequency of association, whereas nascent transcription from the human α-globin gene appears unaffected. We see no evidence that cotranscribed erythroid genes associate at shared transcription foci, but we do see stochastic clustering of active genes around common nuclear SC35-enriched speckles (hence the apparent nonrandom association between genes). Thus, association between active genes may result from their location on decondensed chromatin that enables clustering around common nuclear speckles.
Blood | 2011
Alison T. Merryweather-Clarke; Ann Atzberger; Shamit Soneji; Nicki Gray; Kevin D. Clark; C Waugh; Simon J. McGowan; Stephen Taylor; Asoke K. Nandi; William G. Wood; David J. Roberts; Douglas R. Higgs; Veronica J. Buckle; Kathryn J. H. Robson
Understanding the pattern of gene expression during erythropoiesis is crucial for a synthesis of erythroid developmental biology. Here, we isolated 4 distinct populations at successive erythropoietin-dependent stages of erythropoiesis, including the terminal, pyknotic stage. The transcriptome was determined using Affymetrix arrays. First, we demonstrated the importance of using defined cell populations to identify lineage and temporally specific patterns of gene expression. Cells sorted by surface expression profile not only express significantly fewer genes than unsorted cells but also demonstrate significantly greater differences in the expression levels of particular genes between stages than unsorted cells. Second, using standard software, we identified more than 1000 transcripts not previously observed to be differentially expressed during erythroid maturation, 13 of which are highly significantly terminally regulated, including RFXAP and SMARCA4. Third, using matched filtering, we identified 12 transcripts not previously reported to be continuously up-regulated in maturing human primary erythroblasts. Finally, using transcription factor binding site analysis, we identified potential transcription factors that may regulate gene expression during terminal erythropoiesis. Our stringent lists of differentially regulated and continuously expressed transcripts containing many genes with undiscovered functions in erythroblasts are a resource for future functional studies of erythropoiesis. Our Human Erythroid Maturation database is available at https://cellline.molbiol.ox.ac.uk/eryth/index.html. [corrected].
Journal of Experimental Medicine | 2017
Adam Mead; Wen Hao Neo; Nikolaos Barkas; S Matsuoka; Alice Giustacchini; R Facchini; Supat Thongjuea; Lauren Jamieson; Booth Cag.; N Fordham; C Di Genua; Deborah Atkinson; Onima Chowdhury; Emmanouela Repapi; Nicki Gray; Shabnam Kharazi; Clark S-A.; T Bouriez; Petter S. Woll; T Suda; Claus Nerlov; Jacobsen Sew.
Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs), FLT3 internal tandem duplications (FLT3 ITDs) have recently been suggested to intrinsically suppress HSCs. Herein, single-cell interrogation found Flt3 mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation between Flt3 and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers of phenotypic HSCs, with an even more severe loss of long-term repopulating HSCs, likely reflecting the presence of non-HSCs within the phenotypic HSC compartment. Competitive transplantation experiments established that Flt3-ITD compromises HSCs through an extrinsically mediated mechanism of disrupting HSC-supporting bone marrow stromal cells, with reduced numbers of endothelial and mesenchymal stromal cells showing increased inflammation-associated gene expression. Tumor necrosis factor (TNF), a cell-extrinsic potent negative regulator of HSCs, was overexpressed in bone marrow niche cells from FLT3-ITD mice, and anti-TNF treatment partially rescued the HSC phenotype. These findings, which establish that Flt3-ITD–driven myeloproliferation results in cell-extrinsic suppression of the normal HSC reservoir, are of relevance for several aspects of acute myeloid leukemia biology.
EMBO Reports | 2017
Diu T.T. Nguyen; Hsiao P.J. Voon; Barbara Xella; Caroline Scott; David Clynes; Christian Babbs; Helena Ayyub; Jon Kerry; Jacqueline A. Sharpe; Jackie Sloane-Stanley; Sue Butler; Chris Fisher; Nicki Gray; Thomas Jenuwein; Douglas R. Higgs; Richard J. Gibbons
ATRX is a chromatin remodelling factor found at a wide range of tandemly repeated sequences including telomeres (TTAGGG)n. ATRX mutations are found in nearly all tumours that maintain their telomeres via the alternative lengthening of telomere (ALT) pathway, and ATRX is known to suppress this pathway. Here, we show that recruitment of ATRX to telomeric repeats depends on repeat number, orientation and, critically, on repeat transcription. Importantly, the transcribed telomeric repeats form RNA–DNA hybrids (R‐loops) whose abundance correlates with the recruitment of ATRX. Here, we show loss of ATRX is also associated with increased R‐loop formation. Our data suggest that the presence of ATRX at telomeres may have a central role in suppressing deleterious DNA secondary structures that form at transcribed telomeric repeats, and this may account for the increased DNA damage, stalling of replication and homology‐directed repair previously observed upon loss of ATRX function.
Cancer Research | 2018
Tamara Aleksic; Nicki Gray; Xiaoning Wu; Guillaume Rieunier; Eliot Osher; Jack Mills; Clare Verrill; Richard J. Bryant; Cheng Han; Kathryn Hutchinson; Adam Lambert; Rajeev Kumar; Freddie C. Hamdy; Ulrike Weyer-Czernilofsky; Michael P. Sanderson; Thomas Bogenrieder; Stephen Taylor; Valentine M. Macaulay
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 to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R-binding sites at or near transcription start sites of genes including JUN and FAM21, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF1 also enriched RNAPol2 on promoters containing IGF1R-binding sites. These functions were inhibited by IGF1/II-neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected IGF1R on JUN and FAM21 promoters in fresh prostate cancers that contained abundant nuclear IGF1R, with evidence of correlation between nuclear IGF1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs.Significance: These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs. Cancer Res; 78(13); 3497-509. ©2018 AACR.
Blood | 2018
Petter S. Woll; Natalija Buza-Vidas; Chin Dwl.; Hanane Boukarabila; Tiago C. Luis; L Stenson; Tiphaine Bouriez-Jones; Helen Ferry; Adam Mead; Deborah Atkinson; S Jin; Clark S-A.; B Wu; Emmanouela Repapi; Nicki Gray; Stephen Taylor; A P Mutvei; Y L Tsoi; Claus Nerlov; U Lendahl; Jacobsen Sew.
Although an essential role for canonical Notch signaling in generation of hematopoietic stem cells in the embryo and in thymic T-cell development is well established, its role in adult bone marrow (BM) myelopoiesis remains unclear. Some studies, analyzing myeloid progenitors in adult mice with inhibited Notch signaling, implicated distinct roles of canonical Notch signaling in regulation of progenitors for the megakaryocyte, erythroid, and granulocyte-macrophage cell lineages. However, these studies might also have targeted other pathways. Therefore, we specifically deleted, in adult BM, the transcription factor recombination signal-binding protein J κ (Rbpj), through which canonical signaling from all Notch receptors converges. Notably, detailed progenitor staging established that canonical Notch signaling is fully dispensable for all investigated stages of megakaryocyte, erythroid, and myeloid progenitors in steady state unperturbed hematopoiesis, after competitive BM transplantation, and in stress-induced erythropoiesis. Moreover, expression of key regulators of these hematopoietic lineages and Notch target genes were unaffected by Rbpj deficiency in BM progenitor cells.
Haematologica | 2017
Petter S. Woll; Natalija B-V.; Hanane Boukarabila; L Stenson; Tiphaine Bouriez-Jones; Helen Ferry; Adam Mead; Deborah Atkinson; Supat Thongjuea; S Jin; Clark S-A.; D Chin; T Lu-S; Emmanouela Repapi; Nicki Gray; Stephen Taylor; A P Mutvei; Y L Tsoi; Claus Nerlov; U Lendahl; Jacobsen Sew.
Haematologica | 2017
R Norfo; C Di Genua; C Booth; Alice Giustacchini; Benjamin Povinelli; Nicki Gray; Emmanouela Repapi; Elizabeth J. Soilleux; Lauren Jamieson; N Tran; Anthony R. Green; Sten Eirik W. Jacobsen; Adam Mead
Experimental Hematology | 2016
Catherine Porcher; Hedia Chagraoui; Maiken S. Kristiansen; Johanna Richter; Nicki Gray; Emmanouela Repapi; Stephen Taylor; Paresh Vyas
Experimental Hematology | 2016
Marella de Bruijn; Lucas Greder; Gemma Swiers; Emmanouela Repapi; Stella Antoniou; Emanuele Azzoni; Nicki Gray; Stephen Taylor