Genes are regulated by complex interactions involving transcription factors, DNA regulatory regions, and epigenetic modifications which alter chromatin structure. Modifications to chromatin regulate important biological processes including development and response to environmental signals. Scientists from the European Molecular Biology Laboratory (EMBL) have developed what they describe as a modular epigenome editing platform that uses CRISPR-Cas9 technology to program epigenetic modifications at any location in the genome. Details of their work are published in Nature Genetics in a paper titled, “Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications.”

According to its developers, the CRISPR-based system can program nine biologically important chromatin marks at any desired region in the genome. The scientists also designed a reporter system that allowed them to measure changes in gene expression at the single-cell level, and to understand how changes in the DNA sequence influence the impact of each chromatic mark. 

“Our modular epigenetic editing toolkit constitutes a new experimental approach to dissect the reciprocal relationships between the genome and epigenome,” said Jamie Hackett, PhD, group leader at EMBL Rome and senior author on the paper. “The system could be used in the future to more precisely understand the importance of epigenomic changes in influencing gene activity during development and in human disease. On the other hand, the technology also unlocks the ability to program desired gene expression levels in a highly tunable manner. This is an exciting avenue for precision health applications and may prove useful in disease settings.”

Scientists have studied the effects of specific chromatin marks on gene regulation by mapping their distribution in the genomes of healthy and diseased cells, and combining the data with gene expression and the known effects of perturbing specific genes. However, the causal relationship between chromatin marks and gene regulation is difficult to determine. Using CRISPR, the researchers could alter specific DNA locations and dissect the cause-and-consequence relationships between the chromatin marks and their biological effects.

With their epigenome editing system, the scientists identified interesting roles for chromatin marks like H3K4me3. They observed that it increases transcription by itself if artificially added to specific DNA locations. “This was an extremely exciting and unexpected result that went against all our expectations,” said Cristina Policarpi, PhD, a postdoc in the Hackett group and lead scientist of the study. “Our data point toward a complex regulatory network, in which multiple governing factors interact to modulate the levels of gene expression in a given cell. These factors include the pre-existing structure of the chromatin, the underlying DNA sequence, and the location in the genome.” 

For their next steps, the researchers plan to confirm and expand upon their conclusions by targeting genes across different cell types. They’ll also explore how chromatin marks influence transcription across diverse genes and downstream mechanisms. Lastly, the team is exploring avenues for commercializing their technology through a start-up.

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