In 2014, 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 mitochondria and demonstrated the presence of internal N7-methylguanosines in mRNA using base-resolution sequencing. After completing his Ph.D., Li-Sheng worked as a postdoctoral scholar in Professor Chuan He’s lab, where he developed base-resolution quantitative sequencing technologies to investigate various RNA modifications in mammals. His innovations include BID-seq for RNA pseudouridine, Nm-Mut-seq for RNA 2′-O-methylation (Nm), DAMM-seq for RNA m1A/m3C/m1G/m22G, m7G-seq/m7G-quant-seq for RNA internal m7G, and DR-6mA-seq for DNA 6mA. In late April 2023, Li-Sheng joined HKUST as an Assistant Professor in both Division of Life Science and Department of Chemistry, where he began his independent research in chemical biology, epigenetics, RNA biology, development, cancer biology, and bioinformatics.

Research Question

The Zhang Lab focuses on multiple research directions, including:

1. Quantitative base-resolution sequencing of messenger RNA (mRNA) modifications;
2. Reversible RNA methylation in gene expression regulation;
3. RNA-based therapeutics and RNA delivery;
4. Functional investigations of various RNA modifications in mRNA, chromosome-associated RNA (caRNA), non-coding RNA, mitochondrial RNA, and RNA virus;
5. Computational bioinformatics approaches to decipher the dynamic RNA epitranscriptome.

The Zhang Lab aims to advance research by leveraging expertise in chemical biology, chemistry, genomics, genetics, immunology, RNA biology, cell biology, RNA biochemistry, nucleic acid chemistry, protein engineering, mass spectrometry, next-generation sequencing, and bioinformatics. Our goal is to address fundamental questions related to gene expression regulation across diverse biological processes.

Representative Publications

(† These authors contributed equally; * Corresponding author.)

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. 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).
3. 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).
4. 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).
5. 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).
6. 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).
7. Zhang LS*, Ju CW, Jiang B, He C. Base-resolution quantitative DAMM-seq for mapping RNA methylations in tRNA and mitochondrial polycistronic RNA. Methods in Enzymology 692, 39–54 (2023).
8. 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).
9. 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).
10. Zhang LS, Dai Q, He C*. BID-seq: The Quantitative and Base-Resolution Sequencing Method for RNA Pseudouridine. ACS Chemical Biology 18, 4–6 (2023).
11. 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).
12. Zhang LS, Chen G, Wang X, Guo QY, Zhang XS, Pan F, Chen K, Shi ZJ*. Direct borylation of primary C–H bonds in functionalized molecules by palladium catalysis. Angewandte Chemie International Edition 53, 3899–3903 (2014).
13. Zhang LS, Chen K, Chen G, Li BJ, Luo S, Shi ZJ*. Palladium-catalyzed trifluoromethylation of aromatic C–H bond directed by an acetamino group. Organic Letters 15, 10–13 (2013).
14. Shen S, Zhang LS*. The Regulation of Antiviral Innate Immunity through Non-m6A RNA Modifications. Frontiers in Immunology (2023) DOI: 10.3389/fimmu.2023.1286820.
15. Hu L†,*, Liu S†, Peng Y†, Ge R†, Su R†, Senevirathne C, Harada BT, Dai Q, Wei J, Zhang LS, Hao Z, Luo L, Wang H, Wang Y, Luo M, Chen M*, Chen J*, He C*. m6A RNA modifications are measured at single-base resolution across the mammalian transcriptome. Nature Biotechnology 40, 1210–1219 (2022).
16. He PC†, Wei J†, Dou X†, Harada B†, Zhang Z, Ge R, Liu C, Zhang LS, Yu X, Wang S, Lyu R, Zou Z, Chen M, He C*. Exon architecture controls mRNA m6A suppression and gene expression. Science 379, 677–682 (2023).
17. Li Y†, Yi Y†, Gao X, Wang X, Zhao D, Wang R, Zhang LS, Gao B, Zhang Y, Zhang L, Cao Q*, Chen K*. 2′-O-methylation at internal sites on mRNA promotes mRNA stability. Molecular Cell 84, 2320–2336 (2024).
18. Liu C†, Dou X†, Zhao Y†, Zhang L, Zhang LS, Dai Q, Liu J, Wu T, Xiao Y, He C. IGF2BP3 promotes mRNA degradation through internal m7G modification. Nature Communications 15, 7421 (2024).