CSH Molecular Case Studies
Hi-C provides information on 3D genome conformation, but it can also be used to detect genetic structural variants. Here, we describe how we used Hi-C to detect structural variants of clinical significance in peripheral blood of pediatric leukemia patients.
It is not currently understood whether and how the genetic background of a cell influences its epigenetic landscape. Here, we developed a computational tool that enables the use of single-cell ATAC to infer CNVs. We have used this tool to demonstrate that genetics impacts chromatin organization of individual cells and their functional output.
Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer
Lineage transformation between lung cancer subtypes is a poorly understood phenomenon associated with resistance to treatment and poor patient outcomes. Here, we aimed to model this transition to define underlying biological mechanisms and identify potential avenues for therapeutic intervention.
Dysregulation of Chromatin Organization in Pediatric and Adult Brain Tumours: Oncoepigenomic Contributions to Tumorigenesis and Cancer Stem Cell Properties
The three-dimensional (3D) organization of the genome is a crucial enabler of cell fate, identity, and function. In this review, we will focus on the emerging role of altered 3D genome organization in the etiology of disease, with a special emphasis on brain cancers.
Single-Cell Chromatin Accessibility Profiling of Glioblastoma Identifies an Invasive Cancer Stem Cell Population Associated With Lower Survival
Chromatin accessibility discriminates stem from mature cell populations, enabling the identification of primitive stem-like cells in primary tumours, such as glioblastoma (GBM) where self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic intervention.
Single-cell epigenomic assays have tremendous potential to illuminate mechanisms of transcriptional control in functionally diverse cancer cell populations. However, application of these techniques to clinical tumour specimens has been hampered by the current inability to distinguish malignant from non-malignant cells, which potently confounds data analysis and interpretation.
Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor immunity are unclear. In this study, we isolated three bacterial species-Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species-that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer.
Ancestry and Frequency of Genetic Variants in the General Population Are Confounders in the Characterization of Germline Variants Linked to Cancer
BMC Medical Genetics
Pediatric high-grade gliomas (pHGGs) are incurable malignant brain cancers. Clear somatic genetic drivers are difficult to identify in the majority of cases. We hypothesized that this may be due to the existence of germline variants that influence tumour etiology and/or progression and are filtered out using traditional pipelines for somatic mutation calling.
We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating sub-5-kb resolution 3D genome maps by in situ Hi-C. Contact maps at sub-5-kb resolution allow identification of individual DNA loops, domain organization, and large-scale genome compartmentalization.
Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand the mechanisms of tumour evolution in this cancer, we performed whole-genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones.
Journal of Clinical Investigation
Replicative immortality is a hallmark of cancer cells governed by telomere maintenance. Approximately 90% of human cancers maintain their telomeres by activating telomerase, driven by the transcriptional upregulation of telomerase reverse transcriptase (TERT). Although TERT promoter mutations (TPMs) are a major cancer-associated genetic mechanism of TERT upregulation, many cancers exhibit TERT upregulation without TPMs. I
We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating the highest-resolution 3D genome maps to-date for this cancer. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including individual physical interactions between regulatory regions and their target genes.
Subclonal Architecture, Evolutionary Trajectories and Patterns of Inheritance of Germline Variants in Pediatric Glioblastoma
Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. Intratumoral genetic heterogeneity and mode of tumour evolution have not been systematically addressed for this cancer. Whole-genome sequencing of germline-tumour pairs showed that pGBM is characterized by intratumoral genetic heterogeneity and consequent subclonal architecture.
Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours.
MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin
Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumours. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed-lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favouring tumorigenic and self-renewing properties.
Ependymomas are common childhood brain tumours that occur throughout the nervous system but are most common in the pediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival.
Fusion of TTYH1 With the C19MC microRNA Cluster Drives Expression of a Brain-Specific DNMT3B Isoform in the Embryonal Brain Tumor Etmr
Embryonal tumours with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumours characterized by high-level amplification of the microRNA cluster C19MC. We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumours, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumours and normal tissues.
Glioblastoma growth is driven by cancer cells that have stem cell properties, but molecular determinants of their tumorigenic behaviour are poorly defined. In cancer, altered activity of the epigenetic modifiers Polycomb and Trithorax complexes may contribute to the neoplastic phenotype. Here, we provide the first mechanistic insights into the role of the Trithorax protein mixed-lineage leukemia (MLL) in maintaining cancer stem cell characteristics in human glioblastoma.