Jing Crystal Zhao's Research Focus
Gene expression regulation lies at the heart of all biological processes and its dysregulation leads to a myriad of human disorders. Recently, chemical modification on messenger RNA (mRNA) has emerged as a novel gene regulatory mechanism and is the research focus of my laboratory. We are investigating how a highly abundant mRNA modification, named N6-methyladenosine (m6A), regulates normal development and cancer.
Jing Crystal Zhao's Research Report
Identification of m6A “writer” and discovery that m6A regulates mRNA stability. m6A has been called the “fifth” nucleotide, due to its abundance on messenger RNA (mRNA), which was reported in the 1970s. Nonetheless, its function had remained unknown. In 2014, together with other labs, we reported the identification a heterodimer consisting of methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14), which together functioned as an m6A methyltransferase. We then discovered that m6A modification catalyzed by this complex destabilizes mRNAs encoding proteins that drive mouse embryonic stem cells (mESCs) differentiation, but that m6A modification did not appear to regulate pluripotency genes in mESCs. This discovery was among the first to define a function for m6A and illustrated the developmental relevance of the modification.
Wang Y, Li Y, Toth JI, Petroski MD, Zhang Z, Zhao JC*. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nature Cell Biology. 2014, 16(2):191-8. DOI: 10.1038/ncb2902. PMCID: PMC4640932
Wang Y, Zhao JC*. Update: Mechanisms Underlying N6-Methyladenosine Modification of Eukaryotic mRNA. Trends in Genetics. 2016, 32(12):763-773. DOI: 10.1016/j.tig.2016.09.006. PMCID: PMC5123927
Dixit D, Xie Q, Rich JN*, Zhao JC*. Messenger RNA Methylation Regulates Glioblastoma Tumorigenesis. Cancer Cell. 2017; 31(4):474-475. DOI: 10.1016/j.ccell.2017.03.010
Discovery that m6A interacts with histone modifications to regulate embryonic neural stem cell proliferation and self-renewal. To understand the role of m6A in development, we deleted METTL14, a critical component of m6A methyltransferase, in embryonic neural stem cells (NSCs) in a mouse model. Phenotypically, NSCs lacking METTL14 display markedly decreased proliferation and premature differentiation, suggesting m6A modification enhances NSC self-renewal. Decreased NSC pool led to decreased number of late-born neurons during cortical neurogenesis. Mechanistically, we discovered a genome-wide increase in specific histone modifications in METTL14 knockout vs. control NSCs. These changes correlated with altered gene expression and observed cellular phenotypes, suggesting functional significance of altered histone modifications in knockout cells. Overall, our study demonstrated an essential role of m6A in development and revealed m6A-regulated histone modifications as a novel gene regulatory mechanism in mammalian cells.
Wang Y, Li Y, Yue M, Wang J, Kumar S, Wechsler-Reya R, Zhang Z, Ogawa Y, Kellis M, Duester G, Zhao JC*. N6-methyladenosine RNA modification promotes embryonic neural stem cell self-renewal through histone modifications. Nature Neuroscience 2018 Feb;21(2):195-206.
Development of microarray-based technology to detect m6A in small amounts of RNA. Current methods used to detect m6A are antibody-based, often resulting in contamination with false positive signals. To devise an alternative method, we developed a microarray-based technology to map m6A sites based on our observation that m6A interferes with pairing of adenosine with uridine or thymidine (A-U/T pairing). Sites mapped in this study are highly abundant in the transcriptome, suggesting that their function warrants future investigation.
Li Y#, Wang Y#, Zhang Z, Zamudio AV, Zhao JC*. Genome-wide detection of high abundance N6-methyladenosine sites by microarray. RNA. 2015, Jun 19, Aug. 21 (8): 1511-8. DOI: 10.1261/rna.051474.115. PMCID: PMC4509940
Jing Crystal Zhao's Bio
Jing Crystal Zhao received her Ph.D. in Endocrinology from the Biology Department at Boston University. She was trained as a research fellow at Massachusetts General Hospital/Harvard Medical School in neuroendocrinology, RNA biology, and epigenetics. She was recruited to the SBP as an Assistant Professor in 2011.