New Tool Reveals How RNA Organizes Inside Cells

The complex environment inside every cell is filled with proteins and nucleic acids like RNA, all performing specific functions in a tightly coordinated sequence. When these molecules do not operate as intended, diseases such as ALS, Huntington’s, or various cancers can develop. Understanding the precise events inside this crowded cellular space, especially during malfunctions, has long challenged scientists. Recently, chemists at the University of Massachusetts Amherst introduced a new tool known as iConRNA. Described in Proceedings of the National Academy of Sciences, this tool offers an in-depth view into RNA’s behavior within the cell and might help explain the origins of several debilitating diseases.

A cell’s interior can be compared to a bustling intersection filled with organelles such as lysosomes, the nucleus, Golgi apparatus, and mitochondria, each protected by its own membrane. Alongside these protected spaces are segments of unshielded proteins and RNA weaving among the organelles, much like pedestrians and cyclists moving through busy city traffic. For years, scientists questioned how these unenclosed molecules could cluster to form membrane-less organelles and remain separated until needed. In 2009, it was discovered that such elements can condense into protected droplets through phase separation, a process similar to oil separating from water.

These droplets, known as biomolecular condensates, can dynamically phase separate under various cellular conditions, and their dysfunction has been associated with many human diseases. Essential to condensate formation are flexible biomolecules such as single-strand RNA and intrinsically disordered proteins, both crucial for cellular activity yet difficult to investigate in detail. Previous models only offered low-resolution perspectives, limiting understanding of the fine molecular processes at play. Until now, no efficient high-resolution tool allowed researchers to examine how phase separation occurs within RNA condensates.

“This is a topic with intense interest in the field,” says Jianhan Chen, the paper’s senior author. “It’s not for lack of effort that a model like ours, iConRNA, hasn’t existed until now; it’s just that it’s extremely hard to build.”

Part of what makes their model so powerful is that it resolves the balance of the distinct physical driving force of phase separation and can also predict how this balance is tuned under different cellular situations. “It allows you to ‘turn the knob’ of things like temperature and salt to see how they affect RNA’s phase separation,” Chen says.

Its performance tracks closely to experimental observations conducted in the lab, which means that, for the first time, researchers can get a close look at one of the enduring mysteries inside every human cell.