Chemical Biology, Genetics
The University of Chicago
Dr. He is also the John T. Wilson Distinguished Service professor of chemistry, biochemistry, and molecular biology, and director of the Institute for Biophysical Dynamics at the University of Chicago.
Reversible RNA and DNA Methylation
Growing up in southwest China, Chuan He would climb mountains, collect plants, and gaze up at the night sky. "I would look at the stars and wonder, is there a boundary to the universe?"
His father, a doctor, and mother, who studied chemistry, worked in an old-fashioned industrial plant. He attended a nontraditional school that tolerated curiosity and freedom of inquiry. These early influences fueled a "strong desire to find something interesting, exciting, and new."
As a result, his later discoveries have not been confined to a narrow area of research, but have hopscotched across several fields, including chemical biology, epigenetics, cell biology, bioinorganic chemistry, structural biology, microbiology, and genomics. He's work has shed light on the role of metals in biological systems and identified bacterial regulators of virulence and antibiotic resistance. Most recently, he's been breaking ground in fundamental biology with the discovery of a new type of gene expression regulation.
He did his PhD research in synthetic chemistry at the Massachusetts Institute of Technology and studied chemical biology as a postdoctoral fellow at Harvard University. "Both of my advisors tended to take on multiple research directions," says He. "Their example gave me a spirit of fearlessness to explore new areas."
That spirit helped when he challenged conventional wisdom by proposing an alternative way that cells create variations through epigenetic modifications. For example, without changing the DNA message itself, cells can regulate how the script is read through the processes of methylation and demethylation—adding or removing methyl groups to molecules. A methyl group consists of a carbon atom bonded to three hydrogens. Reversible methylation of DNA is known to influence how the genetic code is read and to affect normal physiological functions as well as cancer.
In 2011, He's group at the University of Chicago and collaborators showed that reversible modifications to RNA exist and can have similar effects. "I had a hard time publishing this," He admits. "No one had ever heard of it. Until now, no one had shown that RNA modifications could be reversed and could impact genetic information flow."
The researchers focused on one of the most common modifications of human messenger RNA, methylation of the nucleoside adenosine. He and his colleagues showed that adenosine methylation is reversible and can affect protein levels in cells. "It is another chemical handle that mammalian cells reversibly install to tune protein expression," He explains.
The investigators determined that a protein called FTO (fat mass and obesity-associated protein), which is a major player in obesity and type II diabetes, removes methyl groups from adenosine. They dubbed it "the first RNA demethylase." Specialists in metabolic diseases said that this advance in understanding FTO function could aid the development of new anti-obesity therapies. Subsequently, He's group identified a similar protein, ALKBH5, which appears to regulate processes that control the formation of sperm in mice.
These and other results from his lab, He says, "indicate the presence of a new mode of biological regulation through reversible RNA methylation in mammalian cells, which we hope to establish as a new paradigm of gene expression regulation." His group continues work in a number of other areas, but as an HHMI investigator, He plans to concentrate on the implications of reversible RNA modification, calling it "an emerging frontier."