Beyond On and off: Research Reveals Graded Gene Expression in Cells
For decades, the prevailing scientific understanding held that cells solidify their identity by fixing genes in either an “on” or ”off” state through a process called DNA methylation. This mechanism was believed to ensure cellular specialization, preventing a skin cell, for instance, from transforming into a neuron. However, new research from MIT challenges this long-held “dogma,” demonstrating that cells can stably maintain gene expression at numerous points along a spectrum, rather than being limited to binary states.
Domitilla Del Vecchio, a professor of mechanical and biological engineering at MIT, and her team observed this unexpected phenomenon while engineering hamster ovarian cells to express a target gene at varying levels. Cells exhibited a range of activity – from bright fluorescence indicating high gene expression, to dim glows representing weaker expression, and complete absence of fluorescence signifying gene silencing.
Contrary to expectations,a short burst of DNA methylation did not drive gene activity towards either extreme. Instead, cells consistently maintained their initial level of expression. Researchers observed a continuous spectrum of fluorescence intensity,confirming that gene expression is “graded,” or analog,rather than simply “on” or “off.”
This finding builds upon earlier hints of partial gene expression, previously considered a transient condition. the MIT team demonstrated that these intermediate expression levels could persist for over five months, establishing their stability. sebastian Palacios, a lead author of the study, highlighted the surprise: “We found there was a spectrum of cells that expressed any level between on and off. And we thought,how is this possible?”
The implications of this discovery are significant.Del Vecchio suggests that cells may define their identity by locking genes at specific levels of expression, potentially revealing a far greater diversity of cell types than currently recognized. This nuanced understanding could be crucial in unraveling the complexities of health and disease.
The research also offers new perspectives on cancer and therapy resistance, where cells’ ability to shift states allows them to evade treatment. Furthermore, it provides synthetic biologists with novel tools for precisely designing tissues and organs.Michael Elowitz, a professor at Caltech unaffiliated with the study, lauded the work as demonstrating “how analog memory arises through chemical modifications to the DNA itself,” suggesting potential for repurposing this natural mechanism in synthetic biology. Palacios described the discovery as “mind-blowing,” anticipating its relevance across numerous biological processes.The research was supported by funding from the National Science Foundation,MODULUS,and a Vannevar Bush Faculty Fellowship through the U.S. Office of Naval Research.