Newly discovered mechanisms our bodies use to control the reading of genetic material took center stage at NIEHS May 15, in a seminar presented by Chuan He, Ph.D., director of the University of Chicago Institute for Biophysical Dynamics and a Howard Hughes Medical Institute investigator. He is a pioneer and world leader in the study of reversible chemical modifications of DNA and RNA.
Studies yield new findings
He's lab has developed novel methods and tools to detect and map chemical modifications in nucleic acids. His interest in DNA methylation dynamics over the last decade has led to new questions concerning the potential roles of RNA methylation and the discovery that, like DNA, RNA is also reversibly modified in our bodies.
That discovery involved uncovering protein activities responsible for adding and removing those RNA chemical modifications. The first was a protein known to be associated with obesity in humans, called FTO. He’s research group demonstrated that FTO removes a specific chemical mark from RNA that involves methyl group modifications, so it is known as an RNA demethylase.
"Since He’s discovery of the activity of FTO, researchers have become aware that chemical modifications to RNAs control many aspects of biology, such as virus defense, embryogenesis and development, cancer development, and metabolism," said Fred Tyson, Ph.D., from the NIEHS Genes, Environment, and Health Branch. Tyson hosted He's talk for the Keystone Lecture Seminar Series.
New mechanisms in human health
He further showed that chemical modifications to RNA are recognized by specific proteins. In turn, those proteins affect the speed at which RNA is used and degraded. By this process, the chemical modifications serve as marks that control production of the protein encoded for by that particular RNA.
"Bursts in protein expression during a short period of time, such as during narrow windows of embryonic development, are hallmarks in higher organisms that need to be coordinated," He pointed out. "We believe RNA methylation offers a fundamental mechanism to coordinate translation and decay of key transcripts responsible for expressions of these proteins."
Consequently, many human diseases could result from disturbances in how chemical modifications of RNA is handled. "It is very likely that this dynamic process is also altered by the environment and toxic compounds," suggested Leroy Worth Jr, Ph.D., a Department of Extramural Research and Training scientific review officer.
Studies on human diseases and exposures
Using blood samples from patients with certain cancers, He looked for DNA from cells that have died and released their DNA into the bloodstream, called cell-free DNA, which has specific chemical modifications. With this noninvasive method, He and his team were able to identify individuals with colon cancers with a high degree of sensitivity and specificity.
They extended the approach to liver, gastric, and several other cancers with similar results, suggesting that it may be helpful in a broad range of diagnosis and prognosis applications. "This tool could be used as an inexpensive, reliable, and robust approach to find biomarkers for many human diseases and environmental exposures," He said.
Researchers from NIEHS were excited about the prospect of using such tools to study the mechanisms and role of the environment in human health. "He's research has pioneered emerging new areas of study that might be of central importance to understand toxicities associated with environmental exposures," Tyson explained.
Zhao BS, Wang X, Beadell AV, Lu Z, Shi H, Kuuspalu A, Ho RK, He C. 2017. m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition. Nature 542(7642):475–478.
Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C. 2011. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7(12):885–887.
(Douglas Ganini da Silva, Ph.D., is a research fellow in the NIEHS Free Radical Metabolism Group.)