In a surprising twist of biological fate, researchers at Cornell University have uncovered a new role for DNA packaging structures known as nucleosomes. Traditionally viewed as impediments to gene expression, these structures have now been found to alleviate torsional stress in DNA strands, thereby facilitating the decoding of genetic information. This groundbreaking discovery was published on December 18 in the journal Science.
Michelle Wang, the James Gilbert White Distinguished Professor of the Physical Sciences at Cornell, led the research. “If gene expression does not proceed properly, it will lead to all kinds of problems. Abnormal cellular growth, cancer development, and other disorders – they’re all interconnected,” Wang explained. “Gene expression is at the heart of the central dogma of biology, and how that’s regulated dictates everything that’s coming downstream. I think we’re filling in a piece of the puzzle for something really fundamental that affects so many things.”
Understanding Gene Expression
Gene expression is a complex process essential for cellular function, involving the decoding, copying, and dissemination of DNA information via RNA. A crucial step in this process is transcription, where RNA polymerase moves along the DNA strand, copying its code. However, the helical structure of DNA poses a challenge akin to unwinding a tightly coiled rope: as one section is unwound, the rest becomes tighter, creating torsional stress.
Nucleosomes, the basic units of DNA packaging, have long been seen as obstacles that RNA polymerase must overcome. Yet, Wang’s research reveals that these structures, which wrap DNA in a left-handed direction, actually help relieve the torsional stress that builds up during transcription. This discovery sheds light on how complex biological functions can emerge from the simple physical properties of biomolecules.
Innovative Techniques and Discoveries
Wang’s lab has spent decades developing the tools necessary to understand the mechanics of DNA interactions. They invented the angular optical trap and magnetic tweezers, which allow researchers to manipulate DNA strands and measure torque and angular orientation on a molecular scale. These tools have been instrumental in revealing the role of nucleosomes during transcription.
The team’s recent experiments demonstrate that the opposing chiralities of DNA and nucleosomes work together to alleviate torsional stress. Additionally, topoisomerases, enzymes that act like molecular scissors, assist by making temporary cuts in the DNA to release torsion and then resealing the breaks. “As polymerase moves forward, the chromatin becomes a torsional buffer. It releases that stress to allow transcription to move forward. We are really excited by this discovery,” Wang stated.
Implications and Future Directions
The implications of this research are vast, offering new insights into the fundamental processes of DNA transcription and replication. Wang, a Howard Hughes Medical Institute Investigator, hopes that this support will continue to drive discoveries that expand our understanding of gene expression. “We can take this in so many directions, things like nucleosome modifications and remodeling that could change chromatin mechanical properties, which then change how polymerase can go through a nucleosome,” Wang noted. “There’s so many questions we can ask about gene expression. This is just the beginning.”
Co-authors of the study include former postdoctoral researchers Shuming Zhang and Chuang Tan, postdoctoral researcher Xiaomeng Jia, doctoral students Yifeng Hong and Taryn Kay, senior lecturer Robert Fulbright, research specialist James Inman, professor James Berger and his lab members Joshua Jeong and Glenn Hauk of Johns Hopkins University School of Medicine, and senior investigator Mikhail Kashlev with associates Lucyna Lubkowska and Deanna Gotte of the National Cancer Institute.
The research was supported by the Howard Hughes Medical Institute and the National Institutes of Health, underscoring the collaborative effort and significant investment in understanding the intricacies of gene expression.
