Ratio of the CTCF and RAD21 ChIP-seq signals occurring within interacting enhancers and non-interacting enhancers, anchored at peaks for CTCF, RAD21, and the transcription factors CUX1 and HCFC1 for the K562 cell line.
Breakthrough technology opens the door to identifying new drug targets that could treat many genetic diseases. Scientists at the Gladstone Institutes have invented a new way to read and interpret the human genome. The computational method, TargetFinder, can predict where non-coding DNA-the DNA that does not code for proteins – interacts with genes. This technology helps researchers connect mutations in the so-called genomic “dark matter” with the genes they affect, potentially revealing new therapeutic targets for genetic disorders. Influence of features by region.
(a,b) Feature values (a) and predictive importance (b) for features in promoter, enhancer, and window regions
They looked at fragments of non-coding DNA ie enhancers. Enhancers dictate when and where a gene is turned on. Genes can be separated from their enhancers by long stretches of DNA that contain many other genes. “Most genetic mutations that are associated with disease occur in enhancers, making them an incredibly important area of study,” said Katherine Pollard, PhD. “Before now, we struggled to understand how enhancers find the distant genes they act upon.”
Influence of features by region. close Influence of features by region. (a,b) Feature values (a) and predictive importance (b) for features in promoter, enhancer, and window regions
Scientists originally believed that enhancers mostly affect the gene nearest to them. However, the new study revealed that, on a strand of DNA, enhancers can be millions of letters away from the gene they influence, skipping over the genes in between. When an enhancer is far away from the gene it affects, the 2 connect by forming a 3D loop.
Using machine learning technology, the researchers analyzed hundreds of existing datasets from 6 different cell types to look for patterns in the genome that identify where a gene and enhancer interact. They discovered several patterns that exist on the loops that connect enhancers to genes. This pattern accurately predicted whether a gene-enhancer interaction occurred 85% of the time.
Performing experiments in the lab to identify all of these gene-enhancer interactions can take millions of dollars and years of research. The new computational approach is a much cheaper and less time-consuming way to identify gene-enhancer connections in the genome. The technology also provides insight into how DNA loops form and how they might break in disease. The scientists have offered all of the code and data from TargetFinder online for free.
“Our ability to predict the gene targets of enhancers so accurately enables us to link mutations in enhancers to the genes they target,” said Pollard. “Having that link is the first step towards using these connections to treat diseases.” https://gladstone.org/about-us/press-releases/new-tool-enables-scientists-interpret-%E2%80%9Cdark-matter%E2%80%9D-dna
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