Dr. Zhao has a long-standing research interest in tumor epigenetics and tumor immunology, with a focus on transposable elements such as endogenous retrovirus (ERV). The research directions include:1) Discovery of novel regulators of ERV; 2) Function of ERV regulators in cancers; 3) Spatial biology of transposable elements in tumor tissues.

The scientific contributions include:

1) Identification of the first ERV specific H3K9me3 reader protein TNRC18. This discovery revealed a novel H3K9me3-sensing and regulatory pathway, which operates to epigenetically silence the evolutionarily young ERVs, thereby exerting profound impacts on host genome integrity, transcriptomic regulation, immunity, and development (Zhao*, Lu* et al. Nature, 2023).

2) The regulatory mechanisms of novel chromatin modifications, such as DNA N⁶-mA modification and histone monoaminylation (Li*, Zhao* et al. Nature, 2020; Zhao*, Chuh* et al. PNAS, 2021; Zheng*, Weekley*, Vinson*, Zhao*, Bastle* et al. Nature, 2025).

3) The development of technologies identifying novel chromatin regulatory factors (Zhao*, Yang* et al. PNAS, 2017; Zhao*, Zhang* et al. Cell Reports, 2018; Zhao*, Cheng* et al. Cell Research, 2019).

Collectively, these works contribute to the understanding of TE silencing, gene expression and their effects on cancers (Zhao, Allis, Wang. Nat. Rev. Cancer, 2021). The study of these novel TE silencers in 'immune-cold' cancers provides insights into epigenetic therapy and immunotherapy, raising potential targets for drug discovery.

(*Co-first author; ^#Co-corresponding author)

1. Zhao S*, Lu J*, Pan B, Fan H, Byrum S, Xu C, Kim A, Guo Y, Kanchi K, Gong W, Sun T, Storey A, Burkholder N, Mackintosh S, Kuhlers P, Edmondson R, Strahl B, Diao Y, Tackett A, Raab J, Cai L, Song J^#, Wang G^# (2023) TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons. Nature 623: 633–642

2. Li Z*, Zhao S*, Nelakanti R*, Lin K*, Wu T*, Alderman III M, Guo C, Wang P, Zhang M, Min W, Jiang Z, Wang Y, Li H^#, Xiao A^# (2020) N6-methyladenine in DNA antagonizes SATB1 in early development. Nature 583: 625-630

3. Zheng Q*, Weekley B*, Vinson D*, Zhao S*, Bastle R*, Thompson R, Stransky S, Ramakrishnan A, Cunningham A, Dutta S, Chan J, Salvo GD, Chen M, Zhang N, Wu J, Fulton S, Kong L, Wang H, Zhang B, Vostal L, Upad A, Dierdorff L, Shen L, Molina H, Sidoli S, Muir T, Li H^#, David Y^#, Maze I^# (2025) Histone monoaminylation dynamics are regulated by a single enzyme and promote neural rhythmicity. Nature 637: 974-982

4. Zhao S, Allis CD, Wang G (2021) The language of chromatin modification in human cancers. Nat. Rev. Cancer 21: 413-430 (Cover Story)

5. Zhao S*, Chuh K*, Zhang B*, Xu N, Xue Y, Liu X, Farrelly F, Thompson R, Roeder R, Maze I^#, Muir T^#, Li H^# (2021) Histone H3Q5 serotonylation stabilizes H3K4me3 and potentiates its readout by TAF3. PNAS 118 (6) e2016742118

6. Zhao S*, Cheng L*, Gao Y*, Zhang B*, Zheng X, Wang L, Li P^#, Sun Q^#, and Li H^# (2019) Plant HP1 protein ADCP1 links multivalent H3K9 methylation readout to heterochromatin formation. Cell Research 29 (1): 54-66

7. Zhao S*, Zhang B*, Yang M, Zhu J, and Li H (2018) Systematic profiling of histone readers in Arabidopsis thaliana. Cell Reports 22: 1090-1102

8. Zhao S*, Yang M*, Zhou W, Zhang B, Cheng Z, Huang J. Zhang M, Wang Z, Wang R, Chen Z, Zhu J^#, and Li H^# (2017) Kinetic and high-throughput profiling of epigenetic interactions by 3D-carbene chip-based surface plasmon resonance imaging technology. PNAS 114: E7245-E7254

9. Zhao S, Yue Y, Li Y, Li H (2019) Identification and characterization of “readers” for novel histone modifications. Curr Opin Chem Biol 51: 57-65

10. Zhao S*, Zhang X*, and Li H (2018) Beyond histone acetylation – writing and erasing histone acylations. Curr Opin Struc Biol 53:169–177

11. Xu C, Zhao S, Cai L (2023) Epigenetic (De) regulation in prostate cancer. Springer Books - Chen (ed.) Epigenetics in Oncology: 321-360.

12. Liu X*, Wang J*^, Boyer J, Gong W, Zhao S, Xie L, Wu Q, Zhang C, Jain K, Guo Y, Roderiguez J, Li M, Uryu H, Liao C, Hu L, Zhou J, Shi X, Tsai Y, Yan Q, Luo W, Chen X, Strahl B, Kriegsheim A, Zhang Q, Wang G^#, Baldwin A^#, Zhang Q^# (2022) Histone H3 proline 16 hydroxylation regulates mammalian gene expression. Nat. Genet. 54: 1721-1735

13. Ahn J, Davis E, Daugird T, Zhao S, Quiroga I, Uryu H, Li J, Storey A, Tsai Y, Keeley D, Mackintosh S, Edmondson R, Byrum S, Cai L, Tackett A, Zheng D, Legant W, Phanstiel D^#, Wang G^# (2021) Phase separation drives aberrant chromatin looping and cancer development. Nature 595: 591-595

14. Guo Y, Zhao S, Wang G (2021) Polycomb gene silencing mechanisms: PRC2 chromatin targeting, H3K27me3 'readout', and phase separation-based compaction. Trends Genet 37(6): 547-565 (Cover Story)

15. Farrelly L, Thompson R, Zhao S, Lepack A, Lyu Y, Bhanu N, Zhang B, Loh Y-HE, Ramakrishnan A, Vadodaria K, Heard K, Erikson G, Nakadai T, Bastle R, Lukasak B, Zebroski III H, Alenina N, Bader M, Berton O, Roeder R, Molina H, Gage F, Shen L, Garcia B, Li H, Muir T, Maze I (2019) Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 567: 535–539

16. Zhang X, Cao R, Niu J, Yang S, Ma H, Zhao S, Li H (2019) Molecular basis for hierarchical histone de-β-hydroxybutyrylation by SIRT3. Cell Discovery 5:35

17. Xiong X, Panchenko T, Yang S, Zhao S, Yan P, Zhang W, Xie W, Li Y, Zhao Y, Allis CD, and Li H (2016) Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. Nat Chem Biol 12:1111-1118

18. Zhao D, Guan H, Zhao S, Mi W, Wen H, Li Y, Zhao Y, Allis CD, Shi X, and Li H (2016) YEATS2 is a selective histone crotonylation reader. Cell Research 26:629–632

19. Zhao S and Li H (2015) Crystallography-based mechanistic insights into epigenetic regulation. Elsevier Publisher - Zheng (ed.) Epigenetic Technological Applications: 125-147

20. Li H, Zhao S, and Patel D (2015) Histone recognition by tandem modules and modulation by multiple PTMs. Springer Books - Life Sciences and Biomedicine (ed.) Histone Recognition: 149-172