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Cancer Chromatin Maps Reveal Regulatory Features, Subtype Differences

NEW YORK (GenomeWeb) – A Stanford University-led team has mapped chromatin accessibility in hundreds of human cancer samples, uncovering a range of regulatory interactions involving chromatin epigenome "switches" that seem to alter gene activity at sites relevant to cancer risk and/or treatment outcomes.

"These switches that determine gene activity were our missing component," co-senior and co-corresponding author Howard Chang, a genetics and epithelial biology researcher at Stanford, said in a statement. "We can now find how these switches are changing cancer, including mutations that make the switch get stuck in the on position."

Using "assay for transposases-accessible chromatin" sequencing (ATAC-seq), in combination with available data from the Cancer Genome Atlas study, Chang and his colleagues narrowed in on nearly 563,000 reproducible, transposase enzyme-accessible chromatin accessibility sites across 410 frozen TCGA primary tumor samples representing 23 cancer types.

"Because accessible chromatin is a hallmark of active DNA regulatory elements, ATAC-seq makes it possible to assess the gene regulatory landscape in primary human cancers," Chang and his co-authors wrote in their study, which appeared online today in Science. "Combined with the richness of diverse, orthogonal data types in TCGA, the chromatin accessibility landscape in cancer provides a key link between inherited and somatic mutations, DNA methylation, long-range gene regulation, and, ultimately, gene expression changes that affect cancer prognosis and therapy."

The team noted that nearly two-thirds of the chromatin accessibility peaks found in its pan-cancer analysis lined up with regulatory elements described in the past, though the analysis also revealed regulatory element differences between tumor types and subtypes, particularly when it came to distal element activity, that pointed to new potential molecular subtypes, in some cases.

The analysis also revealed transcription factors with enhanced activity in cancer, DNA methylation differences linked to chromatin accessibility, long-range regulatory interactions that seemed to impact cancer development or progression, and regulatory element activity that appeared to coincide with immune responses to the tumors.

"These data reveal genetic risk loci of cancer predisposition as active DNA regulatory elements in cancer, identifying gene-regulatory interactions underlying cancer immune evasion, and pinpoint non-coding mutations that drive enhancer activation and may affect patient survival," the authors wrote. "As the chromatin accessibility landscape of additional primary cancer samples are profiled, we anticipate the identification of further epigenetic subdivisions with prognostic implications, potentially nominating avenues for therapeutic intervention."

In a related commentary in Science, Jussi Taipale — a biochemistry and genome-scale biology researcher affiliated with the University of Cambridge, the Karolinska Institute, and the University of Helsinki — said the functional genomics strategy at play in the chromatin mapping analysis "can begin to bridge [the] gap in our mechanistic understanding of the tumorigenic process."

Taipale noted that "it will also be necessary to develop analytical methods that can detect genomic features from minor cell populations of from single cells. Without such multi-omic maps at the cell-type level, it will be exceedingly difficult to move from genomics toward understanding the main drivers of the phenotype of individual tumors."

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