The human genome contains more than 20,000 genes, but only a fraction are active in any given cell at a time. Researchers from the Krebs Group at the European Molecular Biology Laboratory Heidelberg have developed an experimental approach to examine how cells determine which genes to activate and when.
The method, called mCHIRA, allows scientists to insert hundreds or thousands of regulatory DNA sequences, including enhancers and promoters, into a specific location in the genome. Researchers can then test how sequences influence transcription factor binding, enhancer accessibility and transcription while controlling for the effects of the surrounding genomic environment. Enhancers are DNA sequences that help regulate gene expression. Proteins known as transcription factors bind to them and increase the likelihood that associated genes become active. The researchers found that when several transcription factors bind to an enhancer, its probability of becoming accessible rises more strongly than when individual transcription factors bind alone. The study combined mCHIRA with single-molecule footprinting, which measures DNA sequence variation and epigenetic marks in individual cells. Analysis was supported by FootprintCharter, a computational framework developed by co-first author Guido Barzaghi with Judith Zaugg’s computational biology group.
First author Valentina Baderna said mCHIRA separates the effects of a regulatory sequence from those of its genomic environment. Group leader Arnaud Krebs said combining synthetic biology and quantitative genomics can break genome complexity into manageable components and reveal the principles connecting DNA sequence to gene regulation. Future integration with artificial intelligence could extend this work to a larger scale.
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The article can be accessed on: Phys.org
Image Credit: Daniela Velasco/EMBL
