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Increasing Our Understanding of the 3D Genome with Region Capture Micro-C

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  • Increasing Our Understanding of the 3D Genome with Region Capture Micro-C

    Researchers at MIT developed a new technique that can map interactions between genes and their regulatory elements with 100 times higher resolution than previously possible. The human genome is mostly composed of regulatory regions that control the expression of genes within a cell. These regions can be located near or far from a target gene, and the genome loops itself in a 3D structure to enable these interactions. The team’s findings suggest that many genes interact with dozens of different regulatory elements, and their method provides an affordable way to study these interactions, potentially leading to new treatments for genetic diseases.

    To achieve high-resolution mapping, the team built on a more recent technology called Micro-C, which uses an enzyme known as micrococcal nuclease to chop up the genome into nucleosome-sized fragments, each containing 150 to 200 base pairs. This uniformity of small fragments grants Micro-C higher resolution over Hi-C, which has been used for over a decade. However, since Micro-C surveys the entire genome, it still does not achieve high enough resolution to identify specific interactions between genes and their regulatory elements, such as enhancers.

    To address this issue, the team developed a more targeted sequencing of the genome’s interactions, which allowed them to focus on specific regions of the genome that contain genes of interest. By targeting regions that span only a few million base pairs, the potential number of genomic sites is reduced by a factor of one thousand, leading to a millionfold decrease in sequencing costs, to around $1,000. The method, known as Region Capture Micro-C (RCMC), can thus produce maps that are 100 times more informative than other published techniques but at a fraction of the cost.

    “Now we have a method for getting ultra-high-resolution 3D genome structure maps in a very affordable manner. Previously, it was so inaccessible financially because you would need millions, if not billions of dollars, to get high resolution,” said Anders Sejr Hansen, Assistant Professor of Biological Engineering at MIT and the study’s senior author. “The one limitation is that you can't get the whole genome, so you need to know approximately what region you're interested in, but you can get very high resolution, very affordably.”

    Focus of study and key findings
    This research focused on five regions with varying sizes, ranging from hundreds of thousands to about 2 million base pairs. These regions were chosen due to interesting features discovered in previous studies, including a well-known gene called Sox2, which plays a crucial role in tissue formation during embryonic development.

    After capturing and sequencing the DNA segments of interest, the researchers discovered numerous enhancers interacting with Sox2. Additionally, they observed interactions between nearby genes and enhancers that were previously unknown. In regions containing multiple genes and enhancers, some genes were found to interact with up to 50 other DNA segments, and on average, each interacting site contacted around 25 others.

    The researchers’ findings reveal a new layer of 3D structure, with many interactions between enhancers and promoters that have not been seen previously. They also suggest that many genes interact with dozens of different regulatory elements, although further study is needed to determine which of those interactions are the most important to regulating a given gene.

    The team believes that their method provides a tool for disentangling the mechanisms driving gene regulation and opens up possibilities for further research in understanding genetic diseases. Determining which genes interact with regulatory elements could help researchers understand how diseases arise and potentially lead to new treatments. Many genetic diseases are caused by variants that appear in these regulatory regions, so understanding how these regions interact with genes is crucial to developing targeted treatments.

    Overall, the team’s new method provides an affordable way to generate ultra-high-resolution 3D genome structure maps, making the study of gene regulation more accessible and revealing a new layer of 3D structure. The team is excited to bring this research tool to the broader scientific community and enable further research into the mechanisms of gene regulation. Read the official publication in Nature Genetics here.

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