For a complete list please see Google Scholar.
Extended-representation bisulfite sequencing of gene regulatory elements in multiplexed samples and single cellsNature Biotechnology, 2021
Shareef SJ, Bevill SM, Raman AT, Aryee MJ, van Galen P, Hovestadt V†, Bernstein BE†.
Here we present an extended-representation bisulfite sequencing (XRBS) method for targeted profiling of DNA methylation. Our design strikes a balance between expanding coverage of regulatory elements and reproducibly enriching informative CpG dinucleotides in promoters, enhancers and CTCF binding sites. Barcoded DNA fragments are pooled before bisulfite conversion, allowing multiplex processing and technical consistency in low-input samples.PubMed • Journal • PDF •
Genome-wide programmable transcriptional memory by CRISPR-based epigenome editingCell, 2021
Nunez JK, Chen J, Pommier GC, Cogan JZ, … , Bernstein BE, Hovestadt V, Gilbert LA†, Weissman JS†.
We present CRISPRoff, a programmable epigenetic memory writer consisting of a single dead Cas9 fusion protein that establishes DNA methylation and repressive histone modifications. Transient CRISPRoff expression initiates highly specific DNA methylation and gene repression that is maintained through cell division and differentiation of stem cells to neurons. The broad ability of CRISPRoff to initiate heritable gene silencing even outside of CGIs expands the canonical model of methylation-based silencing and enables diverse applications including genome-wide screens, multiplexed cell engineering, enhancer silencing, and mechanistic exploration of epigenetic inheritance.PubMed • Journal • PDF •
Medulloblastomics revisited: biological and clinical insights from thousands of patientsNature Reviews Cancer, 2020
Hovestadt V, Ayrault O, Swartling FJ, Robinson GW, Pfister SM, Northcott PA.
This Review discusses recent genomic, epigenomic, transcriptomic and proteomic profiling studies of human medulloblastoma that have advanced our understanding of its disease subgroups. These efforts have provided new insights into the diverse biology of medulloblastomas that will hopefully lead to improved diagnosis and therapy.PubMed • Journal •
Resolving medulloblastoma cellular architecture by single-cell genomicsNature, 2019
Hovestadt V*, Smith KS*, Bihannic L*, Filbin MG*, …, Robinson GW, Bernstein BE†, Suvà ML†, Northcott PA†.
Characterization of medulloblastoma tissues using single-cell transcriptomics shows that the different molecular subtypes consist of distinct developmental phenotypes.PubMed • Journal • PDF •
Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and ImmunityCell, 2019
van Galen P*, Hovestadt V*, Wadsworth II MH, Hughes TK, …, Shalek AK, Aster JC, Lane AA, Bernstein BE.
A combination of transcriptomics and mutational analyses in single cells from acute myeloid leukemia patients reveals the existence of distinct functional subsets and their associated drivers.PubMed • Journal • PDF •
Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seqScience, 2018
Filbin MG*, Tirosh I*, Hovestadt V*, Shaw ML, …, Golub TR, Regev A†, Bernstein BE†, Suvà ML†.
Diffuse midline gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) are an aggressive type of childhood cancer with few options for treatment. Filbin et al. used a single-cell sequencing approach to study the oncogenic programs, genetics, and cellular hierarchies of H3K27M-glioma. Tumors were mainly composed of cells resembling oligodendrocyte precursor cells, whereas differentiated malignant cells were a smaller fraction. In comparison with other gliomas, these cancers had distinct oncogenic programs and stem cell–like profiles that contributed to their stable tumor-propagating potential. The analysis also identified a lineage-specific marker that may be useful in developing therapies.PubMed • Journal • PDF •
DNA methylation-based classification of central nervous system tumoursNature, 2018
Capper D*, Jones DTW*, Sill M*, Hovestadt V*, …, Brandner S, Korshunov A, von Deimling A†, Pfister SM†.
Precise cancer diagnoses are essential to ensure the best treatment plans for patients, but standardization of the diagnostic process has been challenging. The authors present a comprehensive approach for DNA-methylation-based classification of brain tumours. The tool improves diagnostic precision of standard methods, and is made available online for broad accessibility. The results illustrate the potential applications of molecular diagnosis tools.PubMed • Journal • PDF •
The whole-genome landscape of medulloblastoma subtypesNature, 2017
Northcott PA*, Buchhalter I*, Morrissy AS*, Hovestadt V, …, Marra MA†, Pfister SM†, Taylor MD†, Lichter P†.
Medulloblastomas are highly malignant brain tumours that develop during childhood. Paul Northcott and colleagues analysed the whole-genome sequences of 491 medulloblastomas in order to characterize the genomic landscape across tumours and identify new drivers and mutational signatures. Their integrative genomic analyses, including methylation profiling of 1,256 medulloblastomas, identifies subgroup-specific driver mutations and suggests additional tumour subtypes. The authors assign driver mutations to a high proportion of the less well characterized Group 3 and Group 4, which together contribute to more than 60% of all medulloblastomas.PubMed • Journal • PDF •
New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETsCell, 2016
Sturm D*, Orr BA*, Toprak UH*, Hovestadt V*, …, Pfister SM, Ellison DW†, Korshunov A†, Kool M†.
Highly malignant primitive neuroectodermal tumors of the CNS (CNS-PNETs) have been challenging to diagnose and distinguish from other kinds of brain tumors, but molecular profiling now reveals that these cancers can be readily classified into some known tumor types and four new entities with distinct histopathological and clinical features, paving the way for meaningful clinical trials.PubMed • Journal • PDF •
Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencingNature, 2014
Hovestadt V*, Jones DTW*, Picelli S, Wang W, …, Zapatka M, Radlwimmer B†, Pfister SM†, Lichter P†.
Medulloblastoma is the most common malignant childhood brain tumour. Here, the authors present a comprehensive genome-wide DNA methylation data set from human and mouse tumours, coupled with analysis of histone modifications, RNA transcripts and genome sequencing. This integrative analysis uncovers a wealth of alterations in the methylome and should help identify new targets for potential therapeutic intervention.PubMed • Journal • PDF •
Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arraysActa Neuropathologica, 2013
Hovestadt V, Remke M, Kool M, Pietsch T, …, Lichter P, Taylor MD, Pfister SM, Jones DTW
We demonstrate here a method for reliable classification of medulloblastoma into molecular subgroups, and tumour copy-number profiling, using a commercially available DNA methylation array platform that performs well on either frozen or FFPE tumour material. We believe that this platform holds great potential for refining the information obtainable from large, archival tumour series. Most importantly, we also expect that this will become one of the key technologies for risk stratification and patient cohort selection in the next generation of large, biology-led, multi-centre clinical trials.PubMed • Journal • PDF •
Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of GlioblastomaCancer Cell, 2012
Sturm D*, Witt H*, Hovestadt V*, Khuong-Quang DA*, …, Lichter P, Plass C†, Jabado N†, Pfister SM†
Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures.PubMed • Journal • PDF •