The Department of Chemical and Systems Biology Presents

Chuan He, Ph.D.
Department of Chemistry,
Department of Biochemistry and Molecular Biology, and
Institute for Biophysical Dynamics, Howard Hughes Medical Institute
The University of Chicago

“The chemical biology of DNA and RNA methylation” 

 DNA cytosine methylation (5-methylcytosine or 5mC) is a main epigenetic mechanism in human gene expression regulation. This methylation is oxidized by the human TET family enzymes to 5-hydroxymethylcytosine (5hmC) in an active demethylation process. While 5mC is a mark for gene repression in general, recent studies indicate that 5hmC marks active loci. Genomic locations of 5hmC suggest both gene activation and open chromatin state, which could be useful for classifying individual human cells. We have shown that 5hmC-based markers of circulating cell-free DNA (cfDNA) exhibit highly accurate diagnosis value for patients with a range of different human cancers versus healthy controls. These markers also provide unprecedented prognosis advantages and uncover additional signaling pathways previously unrecognized.

We have discovered the first two RNA demethylases, FTO and ALKBH5, which catalyze oxidative demethylation of the most prevalent modifications of mammalian messenger RNA (mRNA) and other nuclear RNA, N⁶-methyladenosine (m⁶A). These findings suggest that reversible RNA modification could impact biological regulation analogous to the well-known reversible DNA and histone chemical modifications. Proteins that selectively recognize m⁶A-modified mRNA and affect the translation status and lifetime of the target mRNA have also been characterized. Functional studies reveal m⁶A methylation as a basic pathway to synchronize groups of transcripts for coordinated metabolism, translation, and decay, allowing timely and coordinated protein synthesis and transcriptome switching during cell differentiation and development. I will present a few examples that RNA methylation controls stem cell differentiation versus self-renewal, affects long-term memory and facilitates cancer immunotherapy.

Reading material: 

1. Michaela Frye, Bryan T Harada, Mikaela Behm, Chuan He.  RNA modifications modulate gene expression during development.  Science 28 Sep 2018: Vol. 361, Issue 6409, pp. 1346-1349. http://science.sciencemag.org/content/361/6409/1346
2. Xiao Wang, Boxuan Simen Zhao, Ian A Roundtree, Kai Chen, Hailing Shi, Chuan He.  N⁶-methyladenosine Modulates Messenger RNA Translation Efficiency.  Cell June 4, 2015.  161, 1388-1399 @2015 Elsevier Inc.  https://www.cell.com/cell/fulltext/S0092-8674(15)00562-0

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