A5030815321- Epigenetics and DNA Methylation
- Hemoglobinopathies and Related Disorders
- Genomics and Chromatin Dynamics
- DNA Repair Mechanisms
- Glioma Diagnosis and Treatment
- Telomeres, Telomerase, and Senescence
- Iron Metabolism and Disorders
- Genetic Syndromes and Imprinting
- Chromatin Remodeling and Cancer
- Genetics and Neurodevelopmental Disorders
- Ubiquitin and proteasome pathways
- Parvovirus B19 Infection Studies
- CRISPR and Genetic Engineering
- RNA modifications and cancer
- Histone Deacetylase Inhibitors Research
- Erythrocyte Function and Pathophysiology
- Acute Myeloid Leukemia Research
- Retinoids in leukemia and cellular processes
- Neonatal Health and Biochemistry
- Genetic and Kidney Cyst Diseases
- Virus-based gene therapy research
- RNA Interference and Gene Delivery
- Endoplasmic Reticulum Stress and Disease
- Neuroblastoma Research and Treatments
Australian Regenerative Medicine Institute
2016-2024
Monash University
2016-2024
John Radcliffe Hospital
2010-2017
University of Oxford
2015-2017
Medical Research Council
2010
The University of Melbourne
2007-2008
Murdoch Children's Research Institute
2006-2008
Royal Children's Hospital
2006-2008
Histone H3.3 is a replication-independent histone variant, which replaces histones that are turned over throughout the entire cell cycle. deposition at euchromatin dependent on HIRA, whereas ATRX/Daxx deposits pericentric heterochromatin and telomeres. The role of heterochromatic regions unknown, but mutations in ATRX/Daxx/H3.3 pathway linked to aberrant telomere lengthening certain cancers. In this study, we show ATRX-dependent not limited telomeres also occurs sites genome. Notably,...
ATRX (alpha thalassemia/mental retardation X-linked) complexes with DAXX to deposit histone variant H3.3 into repetitive heterochromatin. Recent genome sequencing studies in cancers have revealed mutations and their association ALT (alternative lengthening of telomeres) activation. Here we report depletion mouse ES cells leads selective loss ribosomal RNA gene (rDNA) copy number. Supporting this, ATRX-mutated human ALT-positive tumors also show a substantially lower rDNA than ALT-negative...
An array of oncogenic histone point mutations have been identified across a number different cancer studies. It has suggested that some these mutant histones can exert their effects by inhibiting epigenetic writers. Here, we report the H3.3 G34R (glycine to arginine) substitution mutation, found in paediatric gliomas, causes widespread changes H3K9me3 and H3K36me3 interfering with KDM4 family K9/K36 demethylases. Expression targeted single-copy at endogenous levels induced chromatin...
Histone H3.3 is an H3 variant which differs from the canonical H3.1/2 at four residues, including a serine residue position 31 evolutionarily conserved. The S31 phosphorylated (H3.3 S31Ph) heterochromatin regions telomeres and pericentric repeats. However, role of S31Ph in these remains unknown. In this study, we find that regulates accessibility during replication through regulation H3K9/K36 histone demethylase KDM4B. mouse embryonic stem (ES) cells, substitution with alanine A31...
Alternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilised in 15% cancers. ALT cancers are strongly associated with inactivating mutations ATRX; yet loss ATRX alone insufficient to trigger ALT, suggesting that additional cooperating factors involved. We identify H3.3G34R and IDH1/2 as two such ATRX-mutated glioblastomas. Both capable histone demethylases, we KDM4B the key demethylase inactivated ALT. Mouse embryonic stem cells for ATRX, TP53, TERT (KDM4B knockout...
Abstract Background Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events pediatric gliomas. These point affect many chromatin modifications but exact oncogenic mechanisms currently unclear. Histone is known to localize nuclear compartments as promyelocytic leukemia (PML) bodies, which frequently mutated confirmed drivers acute leukemia. Results We find that glioma-associated disrupt formation of PML bodies this...
A primary challenge in lentiviral gene therapy of β-hemoglobinopathies is to maintain low vector copy numbers avoid genotoxicity while being reliably therapeutic for all genotypes. We designed a high-titer vector, LVβ-shα2, that allows coordinated expression the βA-T87Q-globin and an intron-embedded miR-30-based short hairpin RNA (shRNA) selectively targeting α2-globin mRNA. Our approach was guided by knowledge moderate reduction α-globin chain synthesis ameliorates disease severity...
β-thalassemia is an inherited hemoglobinopathy caused by defective synthesis of the β-globin chain hemoglobin, leading to imbalanced globin synthesis. Excess α-globin precipitates in erythroid progenitor cells resulting cell death, ineffective erythropoiesis and severe anemia. Decreased leads milder symptoms, exemplified individuals who co-inherit α- β-thalassemia. In this study, we investigated feasibility utilizing short-interfering RNA (siRNA) mediate reductions expression. A number siRNA...
Abstract α‐Thalassemia represents one of the most important genetic modulators β‐hemoglobinopathies. During this last decade, ongoing interest in characterizing genotype–phenotype relationships has yielded incredible insights into α‐globin gene regulation and its impact on In review, we provide a holistic update expression stemming from DNA to RNA protein, as well epigenetic mechanisms that can potentially influence phenotypic outcomes. Here, highlight defined targeted strategies rationalize...