Our laboratory investigates the molecular mechanisms that coordinate transcription and splicing in human cells. Using cryo-EM, we determined the structure of a transcribing Pol II-U1 snRNP complex, revealing a direct physical interaction between Pol II and the spliceosomal U1 snRNP. This structure revealed that the 5ʹ splice site is positioned close to the RNA exit site of Pol II and provided mechanistic insights into the early steps of co-transcriptional splicing (PMID: 33446560). Recent work from the lab further demonstrates that U1 snRNP is recruited to elongating Pol II through interactions with transcription elongation factors (PMID: 40595577). We also identified a regulatory mechanism that modulates transcription elongation rate, potentially coordinating transcription with RNA processing (PMID: 40624163).
This PhD project aims to define the molecular interactions between the transcription and splicing machineries and to understand how these interactions facilitate efficient and accurate splicing. The student will investigate the structure and function of large co-transcriptional splicing supercomplexes and dissect the mechanisms that coordinate gene expression.
The project will combine biochemical, structural and cellular approaches. The student will gain training in:
- cryo-electron microscopy
- mammalian cell biology including CRISPR-Cas9 genome editing
- in vitro reconstitution of large protein-RNA macromolecular complexes
- biochemical and biophysical assays
The student will join a collaborative research environment focused on mechanistic studies of gene expression and will have access to state-of-the-art cryo-EM, biophysics and mass spectrometry facilities.
Understanding how transcription and RNA splicing are coordinated is fundamental to gene expression and has important implications for diseases such as cancer, where dysregulation of splicing is increasingly recognised.
Please feel free to contact me for more detailed discussion of the project.
Funding Notes
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References
Primary literature:
Zhang S, Aibara S, Vos SM, Agafonov DE, Lührmann R, Cramer P. Structure of a transcribing RNA polymerase II-U1 snRNP complex. Science. 2021 Jan 15;371(6526):305-309. doi: 10.1126/science.abf1870.
Zhang, L., Gordiyenko, Y., Morgan, T., Franco, C., Tufegdžić Vidaković, A., Zhang, S. (2025)Structural basis of RECQL5-induced RNA polymerase II transcription braking and subsequent reactivation.
Nat Struct Mol Biol
Zhang, L., Batters, C., Aibara, S., Gordiyenko, Y., Žumer, K., Schmitzová, J., Maier, K., Cramer, P., Zhang, S. (2025) Structure of a transcribing Pol II-DSIF-SPT6-U1 snRNP complex. Nat Commun 16(1): 5823
Nojima T, Rebelo K, Gomes T, Grosso AR, Proudfoot NJ, Carmo-Fonseca M. RNA Polymerase II Phosphorylated on CTD Serine 5 Interacts with the Spliceosome during Co-transcriptional Splicing. Mol Cell. 2018 Oct 18;72(2):369-379.e4. doi: 10.1016/j.molcel.2018.09.004.
Review:
Tellier M, Maudlin I, Murphy S. Transcription and splicing: A two-way street. Wiley Interdiscip Rev RNA. 2020 Sep;11(5):e1593. doi: 10.1002/wrna.1593.
