INTRODUCTION Cancer is one of the leading causes of death worldwide. Although the 2% of the human genome that encodes proteins has been extensively studied, much remains to be learned about the noncoding genome and gene regulation in cancer. Genes are turned on and off in the proper cell types and cell states by transcription factor (TF) proteins acting on DNA regulatory elements that are scattered over the vast noncoding genome and exert long-range influences. The Cancer Genome Atlas (TCGA) is a global consortium that aims to accelerate the understanding of the molecular basis of cancer. TCGA has systematically collected DNA mutation, methylation, RNA expression, and other comprehensive datasets from primary human cancer tissue. TCGA has served as an invaluable resource for the identification of genomic aberrations, altered transcriptional networks, and cancer subtypes. Nonetheless, the gene regulatory landscapes of these tumors have largely been inferred through indirect means. RATIONALE A hallmark of active DNA regulatory elements is chromatin accessibility. Eukaryotic genomes are compacted in chromatin, a complex of DNA and proteins, and only the active regulatory elements are accessible by the cell’s machinery such as TFs. The assay for transposase-accessible chromatin using sequencing (ATAC-seq) quantifies DNA accessibility through the use of transposase enzymes that insert sequencing adapters at these accessible chromatin sites. ATAC-seq enables the genome-wide profiling of TF binding events that orchestrate gene expression programs and give a cell its identity. RESULTS We generated high-quality ATAC-seq data in 410 tumor samples from TCGA, identifying diverse regulatory landscapes across 23 cancer types. These chromatin accessibility profiles identify cancer- and tissue-specific DNA regulatory elements that enable classification of tumor subtypes with newly recognized prognostic importance. We identify distinct TF activities in cancer based on differences in the inferred patterns of TF-DNA interaction and gene expression. Genome-wide correlation of gene expression and chromatin accessibility predicts tens of thousands of putative interactions between distal regulatory elements and gene promoters, including key oncogenes and targets in cancer immunotherapy, such as MYC , SRC , BCL2 , and PDL1 . Moreover, these regulatory interactions inform known genetic risk loci linked to cancer predisposition, nominating biochemical mechanisms and target genes for many cancer-linked genetic variants. Lastly, integration with mutation profiling by whole-genome sequencing identifies cancer-relevant noncoding mutations that are associated with altered gene expression. A single-base mutation located 12 kilobases upstream of the FGD4 gene, a regulator of the actin cytoskeleton, generates a putative de novo binding site for an NKX TF and is associated with an increase in chromatin accessibility and a concomitant increase in FGD4 gene expression. CONCLUSION The accessible genome of primary human cancers provides a wealth of information on the susceptibility, mechanisms, prognosis, and potential therapeutic strategies of diverse cancer types. Prediction of interactions between DNA regulatory elements and gene promoters sets the stage for future integrative gene regulatory network analyses. The discovery of hundreds of noncoding somatic mutations that exhibit allele-specific regulatory effects suggests a pervasive mechanism for cancer cells to manipulate gene expression and increase cellular fitness. These data may serve as a foundational resource for the cancer research community.

The chromatin accessibility landscape of primary human cancers

DNA methylation is known to be abnormal in all forms of cancer, but it is not really understood how this occurs and what is its role in tumorigenesis. In this review, we take a wide view of this problem by analyzing the strategies involved in setting up normal DNA methylation patterns and understanding how this stable epigenetic mark works to prevent gene activation during development. Aberrant DNA methylation in cancer can be generated either prior to or following cell transformation through mutations. Increasing evidence suggests, however, that most methylation changes are generated in a programmed manner and occur in a subpopulation of tissue cells during normal aging, probably predisposing them for tumorigenesis. It is likely that this methylation contributes to the tumor state by inhibiting the plasticity of cell differentiation processes. Cancer Res; 76(12); 3446-50. ©2016 AACR.

https://cancerres.aacrjournals.org/content/canres/76/12/3446.full.pdf

DNA Methylation in Cancer and Aging.

β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance

Defects in chromatin modifiers and remodelers have been described both for hematological and solid malignancies, corroborating and strengthening the role of epigenetic aberrations in the etiology of cancer. Furthermore, epigenetic marks—DNA methylation, histone modifications, chromatin remodeling, and microRNA—can be considered potential markers of cancer development and progression. Here, we review whether altered epigenetic landscapes are merely a consequence of chromatin modifier/remodeler aberrations or a hallmark of cancer etiology. We critically evaluate current knowledge on causal epigenetic aberrations and examine to what extent the prioritization of (epi)genetic deregulations can be assessed in cancer as some type of genetic lesion characterizing solid cancer progression. We also discuss the multiple challenges in developing compounds targeting epigenetic enzymes (named epidrugs) for epigenetic-based therapies. The implementation of acquired knowledge of epigenetic biomarkers for patient stratification, together with the development of next-generation epidrugs and predictive models, will take our understanding and use of cancer epigenetics in diagnosis, prognosis, and treatment of cancer patients to a new level.

Cancer epigenetics: Moving forward.

Innate and Adaptive Immune Memory: an Evolutionary Continuum in the Host's Response to Pathogens.

We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.

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Néria Verdaguer-Dot

Papers

Whole-genome fingerprint of the DNA methylome during human B cell differentiation