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Dr Chuan He is based at the University of Chicago as the John T Wilson Distinguished Service Professor, director of the Institute for Biophysical Dynamics, and an investigator of the Howard Hughes Medical Institute. His laboratory works on RNA and DNA modifications in gene expression regulation.
We are working on several exciting research projects on RNA modifications: we are currently elucidating the fundamental roles of the N6-methyladenosine (m6A) on mammalian mRNA and have also identified new mRNA modifications and are characterizing their biological functions.
Analogous to histone marks in affecting gene expression, multiple mRNA modifications represent distinct regulatory signals that we believe lead to varied gene expression outcomes at the post-transcriptional level. We are excited to fully elucidate and understand the biological meanings of these marks, particularly how RNA modifications connect to and affect basic biological processes and human diseases.
Lastly, we have been working on developing new, more quantitative technologies to map epitranscriptomes.
Despite extensive recent interest in epitranscriptomics research, the field is still very young and emerging. We are still in the process of discovering new RNA modifications, and defining and characterizing proteins involved in the “writing”, “reading”, and “erasing” of these marks.
The major questions are the functional roles of specific RNA modifications, the impacts of epitranscriptomes on fundamental biological processes and pathways, and how these effects are regulated.
The discovery of FTO as the first RNA demethylase in 2010. I had already been working on oxidative demethylation as a mechanism to mediate DNA methylation damage repair for several years. My colleague Tao Pan in the Department of Biochemistry and Molecular Biology introduced me to the field of RNA biology: we both felt that RNA modifications could be reversible and could play critical roles analogous to epigenetic DNA and histone modifications.
We speculated that the oxidative demethylation mechanism used to repair DNA methylation damage and reverse histone lysine methylations could be used for active RNA demethylation. In 2010, my formal postdoctoral associate Dr Guifang Jia in collaboration with Dr Ye Fu, a graduate student in the group at the time, discovered that FTO, an iron-dependent dioxygenase, can effectively remove the methyl group from m6A in single-stranded RNA and single-stranded DNA.
When Guifang presented the initial data to me, I immediately realized that we had made a potential paradigm-shifting discovery. This work, published in Nature Chemical Biology in 2011, showed for the first time that RNA modifications can be reversed. This initial finding has since sparked the extensive research work on epitranscriptome since.
What are the biggest challenges facing your research at the moment?
I will say at present we face two challenges. We now know that certain RNA modifications are prevalent and fundamental and that approximately 15% of all possible methylation sites are methylated, based on quantification of total cellular mRNA methylation levels. However, we do not understand the selectivity of this methylation. Nor do we know how the installation, reading, and erasing processes are regulated.
We know that mRNA m6A methylation critically impacts cell differentiation and cell fate, but we do not know how the epitranscriptome regulation is integrated into the cellular signaling and regulation network. We still have a long way to go.
On the technology side, we lack quantitative ways to map most RNA modifications, like the way we map DNA 5-methylcytosine and 5-hydroxymethylcytosine modification using bisulfite-sequencing based approaches. We lack ways to map modifications such as m6A in rare cell populations, which have limited the entire field from studying clinical samples and early development events. Looking forward, these are challenges we face as we look to the future of the field.
I have always liked sports and enjoyed reading. I would say I probably would hope to become a novelist. When I was young I liked to imagine and create stories of my own. I probably can be a decent novelist, enough to make a living, I would hope. I do feel science is a perfect fit for me. As a scientist, one’s imagination has no limit.
I have learned this from many friends who are senior to me: the most important tip is to find important questions that deserve your attention. I was the “unlucky” one; it took me eight years to find the right question for me to study.
My second tip is to be disciplined and persistent. We all know how crucial these traits are to the practice of science.
My last suggestion is to be open-minded. Science is so broad and we never know where science will take us to. Enjoy the ride and focus on important questions.
My lab has been working with Abcam on developing antibodies against the target proteins we were interested in. I was honored to be invited as a keynote speaker for an Abcam meeting last year in Boston. When I was contacted by Abcam to organize a RNA modification and epitranscriptomics meeting I immediately agreed as I think this is a great opportunity to introduce this newly emerged filed to the general biological community.
Although m6A is essential, there are multiple other modifications on mRNA. I would like to see how these marks collectively impact post-transcriptional gene expression regulation. I feel as a field we are in a position similar to the field of histone modifications ten years ago. It would be excellent to see not only continued development of the fundamental biology associated with RNA modifications, but also how these RNA marks affect basic biological processes and human diseases.