In a scientific leap that could pave the way for new treatments for genetic disorders, MIT researchers have developed a technique to map the intricate dance of gene expression in cells. The groundbreaking method hinges on capturing ephemeral RNA molecules, enabling scientists to discern the connections between genes and the regulatory elements that control when and how they're turned on. It's a discovery that promises to deepen our grasp of cellular mechanics and disease progression.
The study, led by MIT Research Assistant D.B. Jay Mahat and published in Nature, shines a spotlight on how genes are activated by enhancers—sections of the genome often located far from the genes they influence. While the human genome may host around 23,000 genes, only a fraction are active at any given moment, regulated by these enhancers. However, studying enhancers has proven challenging due to their transient nature and the small quantities of RNA they produce. "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," stated Phillip Sharp, an MIT Institute Professor Emeritus and member of the Koch Institute for Integrative Cancer Research, according to MIT News.
The investigators employed click chemistry to tag eRNA with molecules, enabling the isolation and analysis of those RNA strands—despite losing some during the process. This meticulous work revealed not only when a gene and its regulatory enhancer fire up but also their synchrony within a cell's life cycle. Unveiling such timing is key to understanding the full picture of genetic expression, especially in diseases where gene regulation goes awry—like cancer or autoimmune disorders.
Identifying which enhancers control which genes is not just a matter of academic curiosity; it has significant implications for medical advancements. The FDA's approval last year of gene therapy for sickle cell anemia—targeting an enhancer to switch on a fetal globin gene—is a case in point. There's potential here to usher in a new epoch of genetic treatments. "This is a tool for creating gene-to-enhancer maps, which are fundamental in understanding the biology, and also a foundation for understanding disease," Mahat told MIT News.
On the theoretical edge, the findings bolster a theory posited by Sharp and colleagues about gene transcription control occurring through condensates—clusters of enzymes and RNA that form a membraneless droplet. Insight into the role of eRNA in these transient structures could reshape our fundamental understanding of cellular function and disease development. Funded by the National Cancer Institute, the National Institutes of Health, and the Emerald Foundation Postdoctoral Transition Award, this research adds a new dimension to the intricate tapestry of the genome that future therapies will likely exploit.
