A new technique developed by MIT researchers allows scientists to map gene-enhancer interactions by studying short-lived RNA molecules.
This method provides insights into gene regulation and holds promise for developing treatments for genetic disorders.
Understanding Gene Activity
Our DNA blueprint, the human genome, contains about 23,000 genes, but only a specific set is active in each cell at a time. Regulatory regions called enhancers, often far from their target genes, influence which genes get turned on. However, their distance makes studying these interactions challenging.
The MIT team created a method to track the activation timing of genes and enhancers within a cell. If a gene and an enhancer turn on around the same time, it suggests the enhancer controls that gene.
This technique has the potential to identify drug targets for genetic diseases, as many disease-linked mutations occur in non-coding regions, potentially affecting enhancers.
The Role of eRNA
Less than 2% of our genome codes for proteins. The remaining portion includes elements like enhancers that regulate gene expression. Interestingly, enhancers are transcribed into RNA molecules called enhancer RNA (eRNA).
Scientists believe eRNA production indicates active communication between an enhancer and its target gene. Measuring eRNA levels could shed light on enhancer activity and target genes.
However, studying eRNA is difficult due to its fleeting presence and lack of a standard capture method. To overcome this, researchers use modified nucleotides with a special tag to isolate eRNA from cells.
The MIT researchers employed a technique called click chemistry to link molecules with specific tags. They designed tagged nucleotides that, when incorporated into eRNA, allowed its capture and analysis. This approach provides a snapshot of actively transcribed enhancers and genes within a single cell.
Gene-Enhancer Timing
Using this technique in mouse embryonic stem cells, the researchers could estimate the start time of a specific region's transcription based on RNA strand length and polymerase speed. This revealed which genes and enhancers were activated simultaneously.
The team also studied cell cycle gene expression in greater detail and confirmed known gene-enhancer pairs. Additionally, they generated a list of potential enhancer-gene pairs for further investigation.
Understanding enhancer-gene relationships is crucial for developing treatments for genetic diseases. For instance, the first gene therapy for sickle cell disease targets an enhancer that controls a fetal globin gene.
The MIT team is now applying this technique to immune cells, aiming to understand mutations linked to autoimmune diseases.
This research aligns with a theory proposed by MIT researchers, suggesting that membraneless compartments called condensates regulate gene transcription.
These condensates might contain eRNA produced by enhancers. The study provides valuable evidence for this theory and advances our understanding of how enhancer-derived RNA functions in gene control.
Sources:
Published 5 June 2024, Nature; “Single-cell nascent RNA sequencing unveils coordinated global transcription”
DOI: 10.1038/s41586-024-07517-7
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