Peiyao Zhao / new team – official start in May/June 2026
Peiyao Zhao / new team – official start in May/June 2026
DEPARTMENT
I earned my undergraduate degree from the University of Oxford, Oxford, the UK, before pursuing doctoral training with Dr David Gilbert at Florida State University, Tallahassee, the USA. My PhD research addressed long-standing questions about the mechanistic interplay between the DNA replication timing programme during the S phase and cellular epigenomic states. After my PhD, I joined Allen Institute, Seattle, the USA, as a computational research scientist, where I developed graph neural network methods to study immune cell regulation in human tissues using multidimensional single cell data modalities. My long-term research goal is to elucidate the sub-cell cycle temporal dynamics of epigenomic regulation and their roles in directing cell fate transitions in development and disease through integrated genomic and computational modelling approaches.
Current projects
Past contribution, current projects and future prospects:
The replication timing (RT) programme, which denotes the temporal order in which DNA is replicated during S phase, is evolutionarily conserved, developmentally regulated and disrupted in disease contexts such as cancer. The RT programme is also highly correlated with epigenomic features such that early replicating chromatin is associated with transcriptionally active histone modifications, open 3D chromatin conformation and interior nuclear localization. Despite the long-standing correlation between the RT program and the other epigenomic features, if and how each causally affects the other had long been elusive. In my PhD, I showed that the abrogation of the RT programme caused widespread alterations in histone modifications and euchromatin/heterochromatin compartmentalization in ensuing cell cycles, revealing a novel determinant of the global epigenome. Conversely, I also showed that loop extrusion, a process by which structural maintenance of chromosome (SMC) protein complexes extrude DNA and shape chromatin 3D organization, can in turn influence the sites of DNA replication initiation during the G1 phase, reinforcing the notion that the causal relationships between genomic form and function are not unidirectional but rather complex and context-dependent. Overall, my past research has causally connected several disparate aspects of chromatin biology, revealing how they mechanistically influence one another.
Our current research programme focuses on the delineation of the precise temporal order and causal hierarchy of chromatin features underlying cell fate determination during human early development with unprecedented sub-cell cycle resolution. Specifically, we aim to uncover how DNA replication features during S-phase, which had by and large been viewed as passive reflections of the cell state but were implicated by our previous work as orchestrators of the epigenome, can actively contribute to cell fate determination. Our current projects revolve around the following enquiries:
1) What are the temporal regulatory cascades linking the RT programme, epigenomic remodelling and gene expression during early human embryonic development, and how do these relationships vary across cell lineages and chromatin contexts?
2) How do 3D chromatin organisational features evolve across different stages of S phase, how persistent is this organisational memory across multiple cell cycles during cell differentiation and what molecular factors maintain this memory?
3) In cell fate aberrations such as tumourigenesis, do RT alterations—long observed in association with disease—occur as a cause or a consequence of epigenomic dysregulation and can the manipulation of either feature reverse these aberrations?
To address these aims, we are leveraging omics and computational approaches to generate highly temporally resolved profiles of multidimensional chromatin features in biological systems of distinct temporal scales, alongside causal neural network models that are broadly applicable to diverse dynamic biological processes. Ultimately, our research will answer fundamental questions of how multiple facets of cell state converge to determine cell fates and will open new avenues for clinically valuable applications, such as in vitro cell state manipulation for therapeutic purposes.
Selected Publications:
- Zhao, P.A.†, Li, R., Adewunmi, T., Garber, J., Gustafson, C., Kim, J., Malone, J., Savage, A., Skene, P., & Li, X.J. (2025). SPARROW reveals microenvironment-zone-specific cell states in healthy and diseased tissues. Cell systems, 16(3), 101235. (†lead corresponding author)
- Emerson, D.J.*, Zhao, P.A.*, Cook, A.L.*, Barnett, R.J., Klein, K.N., Saulebekova, D., Ge, C., Zhou, L., Simandi, Z., Minsk, M.K., et al. (2022). Cohesin-mediated loop anchors confine the locations of human replication origins. Nature 606(7915): 812-819. (*contributed equally)
- Klein, K.N.*, Zhao, P.A.*, Lyu, X*., Sasaki, T., Bartlett, D.A., Singh, A.M., Tasan, I., Zhang, M., Watts, L.P., Hiraga, S.-i., et al. (2021). Replication timing maintains the global epigenetic state in human cells. Science 372, 371-378. (*contributed equally)
- Zhao, P.A.*, Sasaki, T.*, and Gilbert, D.M. (2020). High-resolution Repli-Seq defines the temporal choreography of initiation, elongation and termination of replication in mammalian cells. Genome Biol 21, 76. (*contributed equally)