A5074633674- Hemoglobinopathies and Related Disorders
- Genomics and Chromatin Dynamics
- Iron Metabolism and Disorders
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- Genetics and Neurodevelopmental Disorders
- DNA and Nucleic Acid Chemistry
- Erythrocyte Function and Pathophysiology
- Telomeres, Telomerase, and Senescence
- RNA Research and Splicing
- Genomic variations and chromosomal abnormalities
- RNA and protein synthesis mechanisms
- Cancer-related gene regulation
- RNA Interference and Gene Delivery
- Chromosomal and Genetic Variations
- Acute Myeloid Leukemia Research
- Prenatal Screening and Diagnostics
- Neonatal Health and Biochemistry
- Single-cell and spatial transcriptomics
- Cell Image Analysis Techniques
- Gene Regulatory Network Analysis
- Animal Genetics and Reproduction
- Chromatin Remodeling and Cancer
University of Oxford
2002-2022
John Radcliffe Hospital
2009-2022
Institute for Molecular Medicine
2021
Medical Research Council
1982-2017
MRC Weatherall Institute of Molecular Medicine
2005-2017
Institute of Molecular Medicine
1992-2008
Mahidol University
2006
Monash University
2006
MRC Molecular Haematology Unit
2006
Siriraj Hospital
2006
Abstract Fifteen per cent of cancers maintain telomere length independently telomerase by the homologous recombination (HR)-associated alternative lengthening telomeres (ALT) pathway. A unifying feature these tumours are mutations in ATRX. Here we show that expression ectopic ATRX triggers a suppression pathway and shortening. Importantly ATRX-mediated ALT is dependent on histone chaperone DAXX. Re-expression associated with reduction replication fork stalling, known trigger for HR loss MRN...
We have identified a remote, tissue-specific, positive regulatory element that is of major importance in determining the level human alpha-globin gene expression. Stable transformants containing this DNA segment linked to alpha mouse erythroleukemia cells expressed mRNA at levels are indistinguishable from those seen interspecific hybrids genes their normal context on chromosome 16. Furthermore, all transgenic mice region high erythroid tissues; and one such mouse, readily detectable chains...
We describe a pathogenetic mechanism underlying variant form of the inherited blood disorder α thalassemia. Association studies affected individuals from Melanesia localized disease trait to telomeric region human chromosome 16, which includes α-globin gene cluster, but no molecular defects were detected by conventional approaches. After resequencing and using combination chromatin immunoprecipitation expression analysis on tiled oligonucleotide array, we identified gain-of-function...
The major positive regulatory activity of the human alpha-globin gene complex has been localized to an element associated with a strong erythroid-specific DNase I hypersensitive site (HS -40) located 40 kb upstream zeta 2-globin mRNA cap site. Footprint and gel shift analyses have demonstrated presence four binding sites for nuclear factor GATA-1 two corresponding AP-1 consensus sequence. This region resembles one elements beta-globin locus control in its constitution characteristics; this...
The human genome contains ∼30,000 CpG islands (CGIs). While CGIs associated with promoters nearly always remain unmethylated, many of the ∼9,000 lying within gene bodies become methylated during development and differentiation. Both promoter intragenic may also abnormally as a result rearrangements in malignancy. epigenetic mechanisms by which some but others, same cell, unmethylated these situations are poorly understood. Analyzing specific loci using genome-wide analysis, we show that...
The chromatin remodeling protein ATRX, which targets tandem repetitive DNA, has been shown to be required for expression of the alpha globin genes, proliferation a variety cellular progenitors, chromosome congression and maintenance telomeres. Mutations in ATRX have recently identified tumours maintain their telomeres by telomerase independent pathway involving homologous recombination thought triggered DNA damage. It is as yet unknown whether there central underlying mechanism associated...
Extensive molecular studies have characterized 15 dimorphic and 2 multiallelic genetic markers within the human alpha-globin gene cluster. Analysis of these in 9 populations has shown that locus is remarkably polymorphic therefore an ideal marker on chromosome 16 for construction a linkage map. The combined analysis established haplotypes provide means to study genetics common mutants this novel association conventional restriction fragment length polymorphism haplotype linked, hypervariable...
The major positive regulatory activity of the human alpha-globin gene complex has been localized to an element associated with a strong erythroid-specific DNase I hypersensitive site (HS -40) located 40 kb upstream zeta 2-globin mRNA cap site. Footprint and gel shift analyses have demonstrated presence four binding sites for nuclear factor GATA-1 two corresponding AP-1 consensus sequence. This region resembles one elements beta-globin locus control in its constitution characteristics; this...
It is well established that all of the cis-acting sequences required for fully regulated human alpha-globin expression are contained within a region approximately 120 kb conserved synteny. Here, we show activation this cluster in erythroid cells dramatically affects apparently unrelated and noncontiguous genes 500 surrounding domain, including gene (NME4) located 300 from cluster. Changes NME4 mediated by physical cis-interactions between regulatory elements. Polymorphic structural variation...
Nondeletion forms of hereditary persistence fetal hemoglobin may result from regulatory disorders globin gene expression. The defects in two such conditions were localized by demonstrating a tight genetic linkage between the and polymorphic restriction endonuclease sites within beta-like complex. In one instance, defect probably occurred outside region DNA epsilon- beta-globin genes.
Synthesis of normal human hemoglobin A, alpha 2 beta 2, is based upon balanced expression genes in the alpha-globin gene cluster on chromosome 16 and beta-globin 11. Full levels erythroid-specific activation depend sequences located at a considerable distance 5' to gene, referred as locus-activating or dominant control region. The existence an analogous element(s) upstream has been suggested from observations naturally occurring deletions experimental studies. We have identified individual...