The human genome, an avast repository of approximately 23,000 genes, operates with remarkable precision, activating only a select subset of genes within a cell at any given time. This intricate orchestration of gene expression relies on a complex network of regulatory elements, including regions known as enhancers. These enhancers, often situated far from the genes they regulate, act as crucial control switches, but their distant location has made mapping their interactions a significant challenge.
Now, researchers at MIT have devised an innovative technique to overcome this hurdle, allowing them to observe the precise timing of gene and enhancer activation within a cell. This temporal synchrony between a gene and a distant enhancer provides strong evidence of a regulatory relationship.
“When people start using genetic technology to identify regions of chromosomes that have disease information, most of those sites don’t correspond to genes. We suspect they correspond to these enhancers, which can be quite distant from a promoter, so it’s very important to be able to identify these enhancers,” explains Phillip Sharp, an MIT Institute Professor Emeritus and senior author of the study published in Nature.
The key to this breakthrough lies in capturing and analyzing enhancer RNA (eRNA), elusive molecules transcribed from active enhancers. However, eRNA’s scarcity, short lifespan, and lack of a common molecular tag have made it a challenging target.
To address this, the team, led by MIT Research Assistant D.B. Jay Mahat, turned to click chemistry. By incorporating nucleotides with specific chemical handles into growing eRNA strands, they could efficiently fish out and analyze these molecules, providing a snapshot of active enhancers and genes within a single cell.
“You want to be able to determine, in every cell, the activation of transcription from regulatory elements and from their corresponding gene. This has to be done in a single cell because that’s where you can detect synchrony or asynchrony between regulatory elements and genes,” Mahat elaborates.
This ability to pinpoint the timing of gene expression allowed the researchers to delve into the intricacies of cell cycle regulation and confirm previously known gene-enhancer pairs. Furthermore, they generated a list of 50,000 potential new pairs, opening avenues for further investigation.
The implications of this research extend to the realm of disease treatment. Understanding which enhancers control which genes could pave the way for developing targeted therapies for genetic disorders. The team is already applying their technique to study autoimmune diseases like lupus, focusing on mutations in non-coding regions that may disrupt enhancer function.
This work also lends support to a recent theory proposed by Sharp and colleagues, suggesting that gene transcription is regulated by membraneless droplets called condensates. These condensates, composed of enzymes and RNA, may incorporate eRNA from enhancers, facilitating communication between enhancers and their target genes.
“We picture that the communication between an enhancer and a promoter is a condensate-type, transient structure, and RNA is part of that. This is an important piece of work in building the understanding of how RNAs from enhancers could be active,” Sharp concludes.
This research, funded by the National Cancer Institute, the National Institutes of Health, and the Emerald Foundation, provides a powerful new tool for dissecting the complexities of gene regulation, with the potential to transform our understanding of disease and guide the development of innovative therapies.
Responses (0 )