Chuan He Professor
Born Guizhou, P. R. China, 1972.
University of Science and Technology of China (USTC), B.S., 1994.
Massachusetts Institute of Technology, Ph.D., 2000.
Harvard University, Postdoctoral Fellow, 2000-2002.
University of Chicago,
Assistant Professor 2002-2008.
Associate Professor 2008-2010.
Director, Institute for Biophysical Dynamics, 2012-
Investigator, Howard Hughes Medical Institute (HHMI), 2014-
John T. Wilson Distinguished Service Professor, 2014-
2015 American Association for the Advancement of Science (AAAS) Fellow.
2015 Arthur C. Cope Scholar Award.
2012 Mr. and Mrs. Sun Chan Memorial Award in Organic Chemistry.
2010 American Chemical Society Akron Section Award.
2010 Society of Biological Inorganic Chemistry Early Career Award.
2008 Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease Award.
2007 CACPA Distinguished Junior Faculty Award.
2006 Camille Dreyfus Teacher-Scholar Award.
2005 CAREER Award from the National Science Foundation.
2005 Cottrell Scholar by the Research Corporation.
2005 Arnold and Mabel Beckman Foundation Young Investigator.
2005 Alfred P. Sloan Research Fellowship.
2004 W. M. Keck Foundation Distinguished Young Scholar in Medical Science.
2004 G&P Foundation for Cancer Research Young Investigator.
2003 Research Corporation Research Innovation Award.
2003 Searle Scholar Award.
2001 Davison Prize for The Best Thesis in Inorganic Chemistry, MIT.
2000-2002 Damon Runyon-Walter Winchell Cancer Research Fund Postdoctoral Fellow (Harvard).
1997-1999 Merck/MIT Graduate Fellowship.
Guest Professor, University of Science and Technology of China (USTC).
Guest Professor, Nanjing University of Technology.
Guest Professor, Chinese University of Hong Kong.
Guest Professor, Sun Yat-sen University.
Honorary Professor, Guizhou University.
Joint Professor, Peking University.
OFFICE: GCIS E319B, 929 East 57th Street, Chicago, IL 60637
Our research program spans a broad range of chemical biology, nucleic acid chemistry and biology, epigenetics, and bioinorganic chemistry. We discovered the first RNA demethylase and continue to explore gene expression regulation mediated by dynamic and reversible RNA modifications. We developed enabling tools to map DNA 5-hydroxymethylcytosine (5hmC) and its oxidation derivatives in mammalian genomes and continue to study DNA 5-methylcytosine (5mC) oxidation and demethylation in biological regulation. We revealed the presence of DNA 6-methyladenosine (6mA) in eukaryotic genomes and continue to investigate functional roles played by this new DNA mark in eukaryotes. We study virulence and antibiotic resistance regulation in human pathogens. We also study metal ion homeostasis and selective metal ion recognition by naturally occurring and engineered proteins.
1. Reversible RNA Methylation: towards RNA Epigenetics
Cellular RNAs contain more than a hundred structurally distinct post-transcriptional modifications at thousands of sites. Some RNA modifications are dynamic and may have critical regulatory roles analogous to those of protein and DNA modifications. Understanding the scope and mechanisms of dynamic RNA modifications, thus, represents an emerging research frontier in biology and medicine. The internal N6-methyladenosine (m6A) modification in messenger RNA is one of the most abundant RNA modifications in eukaryotes. This base modification is present in 3-5 sites on average of every mRNA in mammals. Deletion of this ubiquitous modification leads to apoptosis in mammalian cells and arrested development of plant cells. Yet, the functional roles of m6A in mRNA had never been elucidated.
Erasers: In 2011, we reported that m6A in mammalian mRNA can be oxidatively demethylated in vitro and inside cells by FTO (fat mass and obesity-associated protein), a major obesity factor, as the first known RNA demethylase. We subsequently identified ALKBH5 as the second RNA demethylase that controls mammalian spermatogenesis. These and other results from our laboratory indicate the presence of a new mode of regulation through reversible RNA methylation in mammalian cells, which we plan to establish as a new paradigm of post-transcriptional gene expression regulation.
Readers: Our recent work has identified the YTH family proteins as the reader proteins that specifically bind methylated RNA transcripts in mammalian cells. Functional characterizations revealed that YTHDF2 affects cytoplasmic localization and mediates decay of methylated mRNA, YTHDF1 promotes translation of methylated mRNA through facilitating translation initiation, and other readers affecting mRNA storage, transport, and cellular localization. Some of these proteins play essential roles in animal development and human diseases. Just like the interplay between DNA cytosine-methylation and methyl-CpG-binding proteins that regulate gene expression through binding to methylated cytosines, m6A is recognized by these reader proteins to exhibit biological functions. We continue to uncover physiological significance of the mRNA methylation in various cell differentiation and development events and study the underlying mechanisms.
Writers: We have identified a core complex comprised of two catalytically active subunits: METTL3 and METTL14, and an accessory factor WTAP, which mediates cellular m6A RNA methylation. Current work focuses on how the methylation selectivity is achieved.
We are also developing sequencing methods to precisely map the m6A mark transcriptome-wide, and exploring other RNA methylation and demethylation events.
2. DNA Methylation, Hydroxymethylation, and Oxidative Demethylation
DNA is not merely a combination of four genetic nucleobases, namely, A, T, C, and G. It also contains modifications that play crucial roles throughout biology. For example, 5-methylcytosine (5mC), the fifth DNA base which is also a crucial epigenetic mark, constitutes ~2-8% of the total cytosines in human genomic DNA and impacts a broad range of biological functions. Recently, the presence of oxidized 5mC, 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), have been discovered in mammalian cells and tissues as the sixth, seventh, and eighth DNA bases. A group of iron(II)/αKG-dependent dioxygenases, the TET proteins, have been shown to utilize dioxygen to oxidize 5mC to these new base modifications in the mammalian genome. These discoveries strongly indicate 5hmC as another vital epigenetic mark that plays broad roles in gene regulation, and 5fC/5caC as intermediates in active DNA demethylation processes. We have developed effective sequencing technologies (TAB-seq and hmC-Seal) to map the precise locations and dissect the exact functional roles of these newly discovered DNA base modifications. We are also exploring these new DNA marks as potential disease markers.
3. DNA N6-Methyladenosine (6mA or m6dA) in Eukaryotes
Although 5mC and 6mA were discovered as DNA methylations almost at the same time decades ago, most research interests have been dedicated to 5mC for its abundant presence in mammals and higher plants. We have recently found that 6mA displays a unique distribution pattern in several unicellular eukaryotic organisms. It marks transcription start sites (TSS) and exhibits a periodicity that marks the linker regions between adjacent nucleosomes. This new DNA mark has also been found to exist in high eukaryotes including animals. We are currently actively exploring functional roles of 6mA in the eukaryotic genomes.
4. Virulence and Antibiotic Resistance Regulation in Human Pathogens
Staphylococcus aureus and Pseudomonas aeruginosa are human pathogens responsible for most wound and nosocomial infections. The extensive use of antibiotics to treat infections has led to the emergence of high-level resistances in various strains of these pathogens. Virulence suppression provides an alternative strategy to effectively reduce pathogenic potential without asserting selective pressure for developing drug resistances. A recent discovery in our laboratory has identified the MgrA protein as a key virulence regulator in S. aureus. This protein belongs to the MarR family of transcriptional regulators that controls antibiotic resistance and virulence in various bacteria. We demonstrated that the mgrA knockout strain shows a 10,000-fold reduction of virulence in vivo. Subsequently, we discovered that oxidative stress leads to dissociation of MgrA from its promoter DNA. The host immune response to S. aureus infection is to produce reactive oxygen and nitrogen species to counter the pathogen. Our study suggests that the microorganism uses MgrA and related regulatory proteins to sense the oxidative stress response generated by the host and regulate a global defensive response. We plan to fully elucidate the underlying virulence regulation pathways, and exploring strategies to suppress S. aureus virulence by targeting virulence regulation. We are also studying MgrA homologues in S. aureus, P. aeruginosa and other pathogens. Our ultimate goal is to develop new strategies for treating infections.
5. Metal Homeostasis and Selective Metal Ion Recognition by Proteins
The ability to regulate essential or toxic metal ion concentrations is critical for cell survival. We have developed a small molecule that blocks copper trafficking inside mammalian cells through binding to the copper trafficking proteins. The treatment with this small molecule selectively inhibits the growth and proliferation of several types of human cancer cells in animal models. We have also been working on understanding how specific metal ions are recognized and regulated in biological systems. We have elucidated the mechanisms of proteins that exhibit remarkable selectivity toward metal ions such as lead(II), cadmium(II), gold(I), copper(I) and iron(II). Some of these proteins can be converted into genetically encoded fluorescent probes for sub-cellular metal ion imaging in live cells. We also work on engineering proteins that possess high sensitivity and selectivity toward various metal ions including actinides, and developing probes for imaging of cellular small molecules.
Wang, X.; Zhao, B. S.; Roundtree, I. A.; Lu, Z.; Han, D.; Ma, H.; Weng, X.; Chen, K.; Shi, H.; He, C.* N6-methyladenosine modulates messenger RNA translation efficiency. Cell 2015, 161, 1388-1399.
Fu, Y.; Luo, G. Z.; Chen, K.; Deng, X.; Yu, M.; Han, D.; Hao, Z.; Liu, J.; Lu, X.; Doré, L. C.; Weng, X.; Ji, Q.; Mets, L.; He, C.* N6-methyldeoxyadenosine marks active transcription start sites in chlamydomonas. Cell 2015, 161, 879-892.
Greer, E. L.*; Blanco, M. A.; Gu, L.; Sendinc, E.; Liu, J.; Aristizábal-Corrales, D.; Hsu, C. H.; Aravind, L.; He, C.; Shi, Y.* DNA methylation on N-adenine in C. elegans. Cell 2015, 161, 868-878.
Zhang, G.; Huang, H.; Liu, D.; Cheng, Y.; Liu, X.; Zhang, W.; Yin, R.; Zhang, D.; Zhang, P.; Liu, J.; Li, C.; Liu, B.; Luo, Y.; Zhu, Y.; Zhang, N.; He, S.; He, C.; Wang, H.*; Chen, D.* N6-methyladenine DNA modification in Drosophila. Cell 2015, 161, 893-906.
Wang, X.; Lu, Z.; Gomez, A.; Hon, G. C.; Yue, Y.; Han, D.; Fu, Y.; Parisien, M.; Dai, Q.; Jia, G.; Ren, B.; Pan, T.; He, C.* N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 2014, 505, 117-120.
Liu, J.; Yue, Y.; Han, D.; Wang, X.; Fu, Y.; Zhang, L.; Jia, G.; Yu, M.; Lu, Z.; Deng, X.; Dai, Q.; Chen, W.; He, C.* A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 2014, 10, 93-95.
Song, C. X.; Szulwach, K. E.; Dai, Q.; Fu, Y.; Mao, S. Q.; Lin, L.; Street, C.; Li, Y.; Poidevin, M.; Wu, H.; Gao, J.; Liu, P.; Li, L.; Xu, G. L.; Jin, P.*; He, C.* Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell 2013, 153, 678-691.
Zheng, G.; Dahl, J. A.; Niu, Y.; Fedorcsak, P.; Huang, C.-M.; Li, Charles J.; Vågbø, Cathrine B.; Shi, Y.; Wang, W.-L.; Song, S.-H.; Lu, Z.; Bosmans, Ralph P. G.; Dai, Q.; Hao, Y.-J.; Yang, X.; Zhao, W.-M.; Tong, W.-M.; Wang, X.-J.; Bogdan, F.; Furu, K.; Fu, Y.; Jia, G.; Zhao, X.; Liu, J.; Krokan, Hans E.; Klungland, A.*; Yang, Y.-G.*; He, C.* ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell. 2013, 49, 18-29.
Yu, M.; Hon, G. C.; Szulwach, K. E.; Song, C.-X.; Zhang, L.; Kim, A.; Li, X. K.; Dai, Q.; Shen, Y.; Park, B.; Min, J. H.; Jin, P.*; Ren, B.*; He, C.* Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 2012, 149, 1368-1380.
Jia, G.; Fu, Y.; Zhao, X.; Dai, Q.; Zheng, G.; Yang, Y.; Yi, C.; Lindahl, T.; Yang, Y.-G.; He, C.* “N6-methyladesosine in nuclear RNA is a major substrate of the obesity-associated FTO” Nat. Chem. Biol. 2011, 7, 885-887.