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Molecular tests that can determine the tissue of origin of cancers of unknown primary (CUP) are still needed. Here, the authors develop a DNA methylation profiling assay and a machine learning classifier to predict the origin of metastatic tumours in CUP patients using formalin-fixed, paraffin embedded samples.

The long-term effect of prenatal nutrition on gene regulation is largely unknown. Here the authors identify differentially methylated regions in whole blood from individuals exposed to famine early after conception, and show that these epigenetic changes may have adverse metabolic consequences later in life.

Whole-genome bisulphite sequencing data from diverse human cell and tissue types shows that only about 22% of CpGs change their methylation state across these cell types; most of these CpGs are located at gene regulatory elements, particularly enhancers and transcription-factor-binding sites, and these selected regions with dynamic DNA methylation patterns could help to define putative regulatory elements further.

Reduced-representation bisulfite sequencing, optimized for DNA amounts as low as 30 nanograms and robust enough to process DNA extracted from formalin-fixed, paraffin-embedded tissue, allows genome-scale mapping of DNA methylation in many samples.

This is a protocol for profiling the methylome and transcriptome of a single cell by using Smart-seq2 and reduced representation bisulfite sequencing.

A single-cell approach is used to follow the heritable stochastic changes to DNA methylation that occur in primary chronic lymphocytic leukaemia and healthy B cells, allowing the tracing of cell lineage histories and evolution during treatment with ibrutinib.

How traits specific to modern humans have evolved is difficult to study. Here, Gokhman et al. compare measured and reconstructed DNA methylation maps of present-day humans, archaic humans and chimpanzees and find that genes that affect vocal tract and facial anatomy show methylation changes between archaic and modern humans.

This paper describes modifications to standard culture conditions that permit the growth of naive human pluripotent stem cells with reduced genomic instability.

In chronic lymphocytic leukemia (CLL), evolution is driven by transcriptional and epigenetic heterogeneity. Here, the authors integrate epigenomic analyses to show how intra-tumoral epigenetic diversity results in divergent chromatin states in CLL cells, increasing cell-to-cell transcriptional heterogeneity.

Human tumours with mutations in LKB1 and Kras have a specific hypermetabolic state associated with increased DNA methylation, pointing to potential metabolic and epigenetic vulnerabilities of specific tumours.

Reduced representation bisulphite sequencing is used to generate genome-scale DNA methylation maps in mouse gametes and several stages of early, pre-implantation embryogenesis, allowing a base-pair resolution timeline of the changes in DNA methylation during developmental transitions.

A lag in nascent strand DNA methylation contributes to heterogeneous methylation in asynchronous cell populations, but cancer cells and active transcription factor binding sites preserve heterogeneity even after cell cycle arrest.

Alexander Meissner and colleagues use CRISPR/Cas9 genome editing to inactivate the DNA methyltransferases DNMT1, DNMT3A and DNMT3B in human embryonic stem cells (ESCs). They find an essential role for DNMT1 in human ESCs and generate genome-wide maps of the DNA methylation changes that occur following inactivation of these enzymes.

Lineage-specific transcription factors and signalling pathways cooperate with pluripotency regulators to control the transcriptional networks that drive cell specification and exit from an embryonic stem cell state; here, we report genome-wide binding data for 38 transcription factors combined with analysis of epigenomic and gene expression data during the differentiation of human embryonic stem cells into the three germ layers.

Catalytically inactive Cas9 fused to a methyltransferase has emerged as a promising epigenome modifying tool. Here the authors generate a methylation depleted but maintenance competent mouse ES cell line and find ubiquitous off-target activity.

Investigation of FOXA2, GATA4 and OCT4 binding across several cell types provides insights into the genetic determinants and epigenetic effects of pioneer-factor occupancy. The data suggest that FOXA2 samples most of its potential binding sites but is stabilized at only a subset of targets.

Margaret Goodell, Wei Li and colleagues report conditional ablation of the Dnmt3a DNA methyltransferase in hematopoietic stem cells (HSCs) in mice. They show that Dnmt3a is critical for epigenetic silencing of HSC regulatory genes and for HSC differentiation.

Methods for profiling DNA methylation differ in the physical principles used to detect modified cytosines. Harris et al. compare the performances of four sequencing-based technologies for genome-wide analysis of DNA methylation and combine two methods to enable detection of allelic differences in epigenetic marks.

Long-term culture of male embryonic stem cells in naive conditions containing Mek1/2 and Gsk3a/b inhibitors leads to irreversible changes in epigenetic and genomic stability that compromise their in vivo developmental potential.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

Genome-scale DNA methylation profiles have been generated at nucleotide resolution in mammalian cells using a combination of high-throughput bisulphite sequencing and single molecule-based sequencing. The DNA methylation maps cover the vast majority of CpG islands, as well as several other genomic regions, in murine embryonic stem cells, cells derived from ES cells and various primary cells.

Comparison of the methylation patterns of cells in different developmental or disease states can help to elucidate both normal and pathological regulatory mechanisms. Bock et al. evaluate the ability of three sequencing-based methods and one microarray-based technology to detect differentially methylated regions on a genome-wide scale.

Analysis of global remethylation in mouse embryos at several developmental stages identifies an epigenetic landscape that partitions extraembryonic tissues within the embryo and resembles a frequent, global departure in genome regulation in human cancers.

The integrative analysis of epigenetic footprints along consecutive stages of neural progenitors derived from human ES cells reveals regulatory mechanisms that orchestrate stage-specific differentiation.