New Tool Precisely Edits Epigenetic Modifications

Powerful epigenetic editing technology was developed as a result of research by the Hackett group at EMBL Rome. This technology allows for the precise programming of chromatin modifications.

One of the main problems in contemporary biology is trying to understand how genes are controlled at the molecular level. The interplay of DNA regulatory regions, proteins known as transcription factors, and epigenetic modifications - chemical changes that alter chromatin structure—drives this intricate process. The term “epigenome” refers to the collection of epigenetic changes made to a cell's genome.

Researchers from EMBL Rome’s Hackett Group have created a modular epigenome editing platform that allows users to program epigenetic changes at any point throughout the genome, as detailed in a recent study that was published in Nature Genetics.

Thanks to this system, researchers can examine the effects of individual chromatin modifications on transcription, the process by which genes are translated from mRNA to produce proteins.

What is Chromatin?

Histones are positively charged proteins found inside the nucleus of cells that firmly cling to negatively charged DNA. Nucleosomes, which are individual DNA units accompanied by histones, group together to form chromatin, a highly ordered structure.

Since chromatin structure affects the accessibility of DNA regulatory regions to transcription factors - proteins that aid in turning on or off gene expression - it is well known that chromatin structure plays a significant role in gene regulation. To date, it is unknown how much “chromatin marks,” which are chemical alterations of histones and DNA, influence transcription regulation.

It is believed that chromatin modifications play a role in the control of important biological processes like disease, development, and the response to environmental cues.

Previous research has mapped the distribution of particular chromatin marks in the genomes of healthy and diseased cell types to better understand the effects of these marks on gene regulation. Scientists have assigned functions to such chromatin marks by combining this data with gene expression analysis and the known effects of perturbing specific genes.

Determining the exact causal relationship between chromatin marks and gene regulation has been challenging. Analyzing the distinct roles played by the numerous intricate components—such as transcription factors, regulatory DNA sequences, and chromatin marks—that go into this kind of regulation is difficult.

The Hackett Group scientists have created a modular epigenome editing system that allows them to precisely program nine chromatin marks that are important for biology at any desired location in the genome. The system is based on CRISPR, a popular genome editing technique that enables highly accurate and precise modifications to be made to particular DNA locations by researchers.

Thanks to these exact perturbations, they meticulously analyzed cause-and-effect connections between chromatin marks and their biological effects. The researchers also created and used a “reporter system,” which gave them the ability to track variations in gene expression at the single-cell level and comprehend how variations in DNA sequence affect the significance of each chromatin mark. Their findings demonstrate the causal functions of several significant chromatin marks in the control of gene expression.

For instance, H3K4me3, a chromatin mark that was previously thought to be the outcome of transcription, has a new function, according to the researchers. It was observed that if H3K4me3 is synthetically added to specific DNA locations, it can actually increase transcription on its own.

This was an extremely exciting and unexpected result that went against all our expectations. Our data point towards 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.”

Cristina Policarpi, PostDoc and Study Leading Scientist, EMBL

Hackett and associates are presently investigating opportunities to utilize this technology via a potentially lucrative start-up business. The next stage will be to validate and extend these findings by focusing on genes at a large scale and in a variety of cell types. 

It is also unclear how chromatin marks affect transcription across the range of genes and downstream processes. 

Our modular epigenetic editing toolkit constitutes a new experimental approach to dissect the reciprocal relationships between the genome and epigenome. 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.”

Jamie Hackett, EMBL Rome

Source:
Journal reference:

Policarpi, C., et al. (2024) Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications. Nature Genetics. doi.org/10.1038/s41588-024-01706-w

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