Professor Li-Sheng Zhang earned his B.S. in Materials Chemistry from Peking University. He then completed his Ph.D. in Chemistry at The University of Chicago in 2019, with the support of the HHMI International Student Research Fellowship. During his Ph.D. training, Li-Sheng discovered ALKBH7-mediated reversible RNA methylation in mitochondrial polycistronic RNA, which regulates mitochondrial gene expression. During his postdoc training, Li-Sheng developed a suite of base-resolution quantitative sequencing methods to study various RNA modifications, as the first- or corresponding authors: (1) Bisulfite-Induced Deletion sequencing (BID-seq, Nature Biotechnology (2023)) for mapping mRNA Ψ; (2) Ultralow-background BID-seq (Nature Protocols (2023)); (3) Nm-Mut-seq for mapping mRNA 2′-O-methylation (Nm) (Cell Research (2023)); (4) Demethylation-Assisted Multiple Methylation sequencing (DAMM-seq, Nature Cell Biology (2021)) for simultaneous detection of m1A, m3C, m1G, and m22G methylations; (5) m7G-seq for mRNA internal m7G methylation (Molecular Cell (2019)). (6) LIME-seq for mapping dynamic RNA methylation in plasma cell-free RNA (Nature Biotechnology (2025)); (7) CRACI for quantitative base-resolution mapping of dihydrouridine (D) modifications in tRNA and mRNA (Nature Communications (2025)).

By 2025 autumn, Prof. Zhang has published >40 research papers in peer-reviewed journals, which have been cited around 3,000 times. He served as the first or corresponding author in many papers, which have been published in Nature Biotechnology (2 papers), Nature Cell Biology, Nature Protocols, Cell Research, PNAS, Nature Communications, Molecular Cell (2 papers), Accounts of Chemical Research, Angewandte Chemie, Organic Letters, ACS Chemical Biology (2 papers), Frontiers in Immunology, etc.

Research Question

Our “Dynamic RNA Epitranscriptome and Functional RNA Lab (DREFR Lab)” focuses on multiple research directions, including:

1. Quantitative base-resolution sequencing of RNA modifications;
2. Functional investigations of various RNA modifications in mRNA, chromosome-associated RNA (caRNA), and non-coding RNA;
3. Computational approaches to decipher dynamic RNA epitranscriptome.
4. RNA-based therapeutics and RNA delivery.

Representative Publications

1. Zhang LS†, Dai Q†, He C*. Base-resolution sequencing methods for whole-transcriptome quantification of messenger RNA modifications. Accounts of Chemical Research 57, 47–58 (2024).
2. Ju CW, Lyu R, Li H, Wei J, Vitela A, Dougherty U, Kwesi A, Luna A, Zhu X, Shen S, Liu Y, Wang L, Cui X, Xu Y, Jiang B, Ji Y, Xia P, West-Szymanski  DC, Sun C, Zhong Y, Ye C, Moran A, Lehmann C, Pamer E, Zhang W, Bissonnette M*, Zhang LS*, He C* Modifications of microbiome-derived cell-free RNA in plasma discriminates colorectal cancer samples. Nature Biotechnology DOI:10.1038/s41587-025-02731-8 (2025).
3. Ju CW, Li H, Jiang B, Wei J, Zou J, Liu Y, Shen S, Shah H, Ye C, Zhong Y, Ge R, Xia P, Ji Y, Liu S, Yang F, Liu B, Xu Y, Zhang LS*, He C*. Quantitative CRACI reveals transcriptome-wide distribution of RNA dihydrouridine at base resolution. Nature Communications (2025).
4. Zhang LS†, Ye C†, Ju CW†, Gao B, Feng X, Sun HL, Wei J, Yang F, Dai Q*, He C*. BID-seq for transcriptome-wide quantitative sequencing of mRNA pseudouridine at base resolution. Nature Protocols 19, 517–538 (2024).
5. Dai Q†,*, Zhang LS†,*, Sun H†, Pajdzik K†, Yang L, Ye C, Ju CW, Liu S, Wang Y, Zheng Z, Zhang L, Harada BT, Dou X, Irkliyenko I, Feng X, Pan T, He C*. Quantitative sequencing using BID-seq uncovers abundant pseudouridines in mammalian mRNA at base resolution. Nature Biotechnology 41, 344–354 (2023).
6. Chen L†, Zhang LS†, Ye C†, Zhou H, Liu B, Gao B, Deng Z, Zhao C*, He C*, Dickinson B*. Nm-Mut-seq: The base-resolution quantitative method for mapping transcriptome-wide 2’-O-methylations. Cell Research 33, 727–730 (2023).
7. Zhang LS, Xiong QP, Perez SP, Liu C, Wei J, Le C, Zhang L, Harada BT, Dai Q, Feng X, Hao Z, Wang Y, Dong X, Hu L, Wang ED, Pan T, Klungland A, Liu RJ*, He C*. ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing. Nature Cell Biology 23, 684–691 (2021).
8. Zhang Y†, Zhang LS†, Dai Q, Chen P, Lu M, Kairis E, Murugaiah V, Xu J, Shukla R, Liang X, Zou Z, Cormet-Boyaka E, Qiu J, Peeples ME, Sharma A, He C*, Li J*. 5-methylcytosine (m5C) RNA modification controls the innate immune response to virus infection by regulating type I interferons. Proceedings of the National Academy of Sciences USA 119, e2123338119 (2022).
9. Zhang LS†, Liu C†, Ma H, Sun HL, Dai, Q, Luo G, Zhang Z, Zhang L, Hu L, Dong X, He C*. Transcriptome-wide mapping of internal N7-methylguanosine methylome in mammalian mRNA. Molecular Cell 74, 1304–1316 (2019).
10. Zhang LS†,*, Ju CW†, Liu C†, Wei J, Dai Q, Chen L, Ye C, He C*. m7G-quant-seq: Quantitative Detection of RNA Internal N7-Methylguanosine. ACS Chemical Biology 17, 3306–3312 (2022).
11. Feng X†, Cui X†, Zhang LS†, Ye C, Wang P, Zhong Y, Wu T, Zhong Z, He C*. Sequencing of N6-methyl-deoxyadenosine at single-base resolution across the mammalian genome. Molecular Cell 84, 596–610 (2024).