Chuan He

John T. Wilson Distinguished Service Professor of
Websites: He Group Website, Howard Hughes Medical Institute
Contact: chuanhe@uchicago.edu
773-702-5061
Assistant: Jordi Tauler
Office Location:
Room E319B, Gordon Center for Integrative Science, 929 E 57th St, Chicago, IL 60637

Our research program spans a broad range of chemical biology, nucleic acid chemistry and biology, RNA biology, and epigenetics. We discovered the first RNA demethylase and characterized functions of different RNA methylation binding proteins. We uncovered transcriptional and post-transcriptional gene expression regulation pathways mediated by dynamic RNA modifications such as N6-methyladenosine (m6A). We developed enabling methods to map RNA and DNA modifications, and we are exploring functional importance of different RNA modifications in diverse biological systems. We also invent new genomic methods to accurately monitor transcription and chromatin state.

RNA Methylation

Cellular RNAs contain more than a hundred fifty 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 on average in ~3 sites of every mRNA in mammals. This modification has been shown to be critical to cell differentiation, animal development, and a range of biological signaling and stress response. We propose that RNA modifications are used by cells to group hundreds to thousands of transcripts for coordinated translation regulation and transcriptome turnover.

Erasers: In 2011, we reported that m6A in mammalian mRNA can be oxidatively demethylated in vitro and inside cells by FTO (a 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.

Readers: Our recent work has characterized the YTH family proteins as the reader proteins that affect stability and translation of methylated transcripts in mammalian cells. Functional characterizations revealed that YTHDF2 affects cytoplasmic localization and mediates the decay of methylated mRNA, YTHDF1 promotes translation of methylated mRNA by facilitating translation initiation, and other readers affect mRNA storage, transport, and cellular localization. Some of these proteins play essential roles in animal development and critical to human diseases. We continue to uncover the physiological significance of the mRNA methylation in various cell differentiation and development events and their underlying mechanisms.

Writers: We have identified a core complex comprised of two subunits: METTL3 and METTL14, and an accessory factor WTAP, which mediates cellular m6A RNA methylation. Cellular RNA methylation level can have profound impacts on normal cell differentiation and cancer cell proliferation. Our current work focuses on how the methylation selectivity is achieved.

Suppressors: We discovered that global mNA m6A specificity is largely governed by m6A “suppressors” that restrict methylation to specific mRNA sites through targeted silencing of m6A in unmethylated mRNA regions. We identified the Exon Junction Complex (EJC), deposited by spliceosomes upstream of exon boundaries, together with peripheral EJC factor RNPS1, package proximal RNA and protect it from m6A deposition. Our findings indicate that transcript exon architecture broadly determines local mRNA accessibility to regulatory machineries via EJC positioning. Exon length within transcripts is a new functionally significant parameter of post-transcriptional gene expression regulation that could impact mRNA modification and processing, and potentially other regulatory processes

Transcriptional regulation: Our most recent work discovered the presence of m6A in chromatin-associated regulatory RNAs (carRNAs) that include promoter-associated RNAs, enhancer RNAs and repeat RNAs. The m6A methylation regulates levels of these carRNAs and controls transcription and chromatin state. The carRNA m6A could be recognized by different m6A-binding proteins, which recruit different chromatin factors to shape local chromatin state. We further showed that the RNA demethylase FTO mediates m6A demethylation on retrotransposon RNAs to notably regulate local and global chromatin state and affect mammalian and plant development. This new layer transcriptional regulation could have profound impacts on gene expression regulation in a wide range of biological processes.

We are also developing sequencing methods to precisely map the m6A mark and other RNA modifications transcriptome-wide. We are also exploring other RNA methylation and demethylation events.

DNA and RNA Cytosine Methylation and Oxidative

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 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. We have developed effective sequencing technologies to map their precise locations and dissect the exact functional roles of these newly discovered DNA base modifications. We have recently invented new methods to perform highly effective sequencing of DNA 5mC and its derivatives. We are exploring these DNA marks as disease diagnosis and prognosis markers.

Among three TET proteins, TET2 is frequently mutated or downregulated in human cancers. We found that TET2 can mediate both DNA oxidation (through binding with CXXC4/5) at enhancer regions and RNA oxidation (through binding with PSPC1) of repeat RNAs. Our findings reveal that chromatin-associated RNA oxidation, rather than DNA oxidation, by TET2 largely dictates the genome-wide activation and leukemogenesis induced by TET2 deficiency. We also establish a new NSUN2-TET2-MBD6-BAP1 pathway in chromatin and transcription regulation through LTR RNA m5C in mammals, and identify components in this pathway as new drug targets for treating TET2 and IDH mutant human diseases.

University of Science and Technology of China (USTC)
B.S.
1994

Massachusetts Institute of Technology
Ph.D.
2000

Harvard University
Postdoctoral Fellow
2002

University of Chicago
Assistant Professor
2008

University of Chicago
Associate Professor
2010

University of Chicago
Professor

University of Chicago
Director, Institute for Biophysical Dynamics
2017

Howard Hughes Medical Institute (HHMI)
Investigator

University of Chicago
John T. Wilson Distinguished Service Professor

Zou, Z.; Dou, X.; Li, Y.; Zhang, Z.; Wang, J.; Gao, B.; Xiao, Y.; Wang, Y.; Zhao, L.; Sun, C.; Liu, Q.; Yu, X.; Wang, H.; Hong, J.; Dai, Q.; Yang, F.-C.; Xu, M.*; He, C.* “RNA m5C oxidation by TET2 regulates chromatin state and leukemogenesis. Nature 2024, on-line.

He, P. C.; Wei, J.; Dou, X.; Harada, B. T.; Zhang, Z.; Ge, R.; Liu, C.; Zhang, L.-S.; Yu, X.; Wang, S.; Lyu, R.; Zou, Z.; Chen, M.; He, C.* Exon architecture controls mRNA m6A suppression and gene expression. Science 2023, 379, 677-682.

Wei, J.; Yu, X.; Yang, L.; Liu, X.; Gao, B.; Huang, B.; Dou, X.; Liu, J.; Zou, Z.; Cui, X. L.; Zhang, L. S.; Zhao, X.; Liu, Q.; He, P. C.; Sepich-Poore, C.; Zhong, N.; Liu, W.; Li, Y.; Kou, X.; Zhao, Y.; Wu, Y.; Cheng, X.; Chen, C.; An, Y.; Dong, X.; Wang, H.; Shu, Q.; Hao, Z.; Duan, T.; He, Y. Y.; Li, X.; Gao, S.*; Gao, Y.*; He, C.* FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development. Science 2022, 376, 968-973.

Yu, Q.; Liu, S.; Yu, L.; Xiao, Y.; Zhang, S.; Wang, X.; Xu, Y.; Yu, H.; Li, Y.; Yang, J.; Tang, J.; Duan, H. C.; Wei, L. H.; Zhang, H.; Wei, J.; Tang, Q.; Wang, C.; Zhang, W.; Wang, Y.; Song, P.; Lu, Q.; Zhang, W.; Dong, S.; Song, B.*; He, C.*; Jia, G.* RNA demethylation increases the yield and biomass of rice and potato plants in field trials. Nat. Biotechnol. 2021, 39, 1581-1588.

Liu, J.; Dou, X.; Chen, C.; Chen, C.; Liu, C.; Xu, M. M.; Zhao, S.; Shen, B.; Gao, Y.*; Han, D.*; He, C.* N6-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription. Science 2020, 367, 580-586.

Han, D*.; Liu, J.; Chen, C.; Dong, L.; Liu, Y.; Chang, R.; Huang, X.; Liu, Y.; Wang, J.; Dougherty, U.; Bissonnette, M. B.; Shen, B.; Weichselbaum, R. R.; Xu, M. M.*; He C.*. Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells. Nature 2019, 566, 270-274

Zhao, B. S.; Wang, X.; Beadell, A. V.; Lu, Z.; Shi, H.; Kuuspalu, A.; Ho, R. K.; He, C. m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition. Nature 2017, 542, 475-478.

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.

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.

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.

Society of Chinese Bioscientists in America (SCBA) Presidential Award
2024

Wolf Prize in Chemistry
2023

Tetrahedron Prize
2023

Falling Walls Science Breakthrough of the Year, Life Sciences
2023

Ray Wu Award
2022

Faculty Award for Excellence in Teaching and Graduate Mentorship
2022

Arthur L. Kelly Faculty Prize for Exceptional Service in the Physical Sciences Division, University of Chicago
2020

ACS Chemical Biology Lectureship
2019

Paul Marks Prize in Cancer Research
2017

American Association for the Advancement of Science (AAAS) Fellow
2015

Arthur C. Cope Scholar Award
2015

Mr. and Mrs. Sun Chan Memorial Award in Organic Chemistry
2012