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GIS-Led Team Publishes Method for Mapping Genome-Wide Chromatin Interactions

NEW YORK (GenomeWeb News) – Researchers from Singapore and the Netherlands reported in Nature today that they successfully used their ChIA-PET method to map the estrogen receptor alpha-related chromatin interactome in human breast cancer cells.

The team, from the Genome Institute of Singapore and Radboud University used their "chromatin interaction analysis using paired-end tag" sequencing approach — dubbed ChIA-PET — to find interactions between map chromatin interactions in a human breast cancer cell line that had been exposed to estrogen. Their method provides a glimpse of the interplay between the three-dimensional nature of the genome, estrogen receptor alpha function, and gene regulation.

Past chromatin immunoprecipitation studies suggest numerous transcription factor binding sites are located far from the promoters they regulate, the team noted, suggesting the genome's three-dimensional shape plays a larger role in gene expression and regulation than is currently appreciated.

"[M]any scientists hypothesized that chromatin interactions — 3-dimensional loops in DNA — might be what allow these regions to remotely talk to genes," lead author Melissa Fullwood, a post-doctoral researcher at GIS, said in a statement.

Nevertheless, Fullwood and her colleagues argued, it's often unclear which of these long-range interactions are functionally important.

"Although distal binding sites have been shown to regulate transcription by long-range chromatin interactions at a few loci, chromatin interactions and their impact on transcription regulation have not been investigated in a genome-wide manner," they wrote.

For the current study, researchers used ChIA-PET — in conjunction with ChIP-Seq, ChIP-qPCR, and microarray data — to investigate interactions between chromatin interactions related to estrogen receptor alpha, or ERα. The ChIA-PET approach involves cross-linking chromatin interactions with formaldehyde, chromatin immunoprecipitation, and sequencing associated DNA based on paired-end tags.

The team treated a human breast cancer cell line called MCF-7 with estrogen and used ChIA-PET sequences generated using the Illumina Genome Analyzer II to create a map of ERα and chromatin interactions across the genome in the MCF-7 cells. They subsequently verified their initial results using an independent ERα ChIA-PET library created with a different ERα antibody.

Such results suggest that interactions taking place across and between chromosomes contribute to ERα function, the team noted, with their subsequent experiments highlighting the extent to which chromatin interactions participate in the transcriptional activation of ERα-related genes following estrogen hormone signaling.

"These results show us that higher order DNA interactions on a genome scale can explain some of the contradictions in older [cancer] studies," co-author Edison Liu, executive director of the Genome Institute of Singapore, said in a statement. "This work will pave the way for the development of highly specific anti-hormone treatments in breast cancer."

Based on their findings, the team suspects that chromatin interactions represent a key regulatory mechanism in mammalian genomes in general. As such, those involved say the ChIA-PET approach holds promise for understanding DNA interactions and gene regulation in a variety of cell types.

"We expect that this global chromatin interactome map and the ChIA-PET assay will be a valuable starting point for future studies of the three-dimensional architecture of transcription biology in whole genome context," the researchers concluded.

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