Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.

Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma

Reverse genetics in model organisms such as Drosophila melanogaster, Arabidopsis thaliana, zebrafish and rats, efficient genome engineering in human embryonic stem and induced pluripotent stem cells, targeted integration in crop plants, and HIV resistance in immune cells - this broad range of outcomes has resulted from the application of the same core technology: targeted genome cleavage by engineered, sequence-specific zinc finger nucleases followed by gene modification during subsequent repair. Such 'genome editing' is now established in human cells and a number of model organisms, thus opening the door to a range of new experimental and therapeutic possibilities.

/pdf/genome-editing-with-engineered-zinc-finger-nucleases-3i1sf7uaja.pdf

Genome editing with engineered zinc finger nucleases

Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.

/pdf/clonal-evolution-in-relapsed-acute-myeloid-leukaemia-4xykv8qod4.pdf

Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing

Organisms require an appropriate balance of stability and reversibility in gene expression programmes to maintain cell identity or to enable responses to stimuli; epigenetic regulation is integral to this dynamic control. Post-translational modification of histones by methylation is an important and widespread type of chromatin modification that is known to influence biological processes in the context of development and cellular responses. To evaluate how histone methylation contributes to stable or reversible control, we provide a broad overview of how histone methylation is regulated and leads to biological outcomes. The importance of appropriately maintaining or reprogramming histone methylation is illustrated by its links to disease and ageing and possibly to transmission of traits across generations.

/pdf/histone-methylation-a-dynamic-mark-in-health-disease-and-53e9mgdnmh.pdf

Histone methylation: a dynamic mark in health, disease and inheritance

Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.

Distinct Factors Control Histone Variant H3.3 Localization at Specific Genomic Regions

The histone variant H33 is implicated in the formation and maintenance of specialized chromatin structure in metazoan cells H33-containing nucleosomes are assembled in a replication-independent manner by means of dedicated chaperone proteins We previously identified the death domain associated protein (Daxx) and the α-thalassemia X-linked mental retardation protein (ATRX) as H33-associated proteins Here, we report that the highly conserved N terminus of Daxx interacts directly with variant-specific residues in the H33 core Recombinant Daxx assembles H33/H4 tetramers on DNA templates, and the ATRX–Daxx complex catalyzes the deposition and remodeling of H33-containing nucleosomes We find that the ATRX–Daxx complex is bound to telomeric chromatin, and that both components of this complex are required for H33 deposition at telomeres in murine embryonic stem cells (ESCs) These data demonstrate that Daxx functions as an H33-specific chaperone and facilitates the deposition of H33 at heterochromatin loci in the context of the ATRX–Daxx complex

https://www.pnas.org/content/pnas/107/32/14075.full.pdf

Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres

New functions for an old variant: no substitute for histone H3.3

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Distinct Factors Control Histone Variant H3.3 Localization at Specific Genomic Regions

Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres

New functions for an old variant: no substitute for histone H3.3