Cryo-EM and mechanistic analysis of co-transcriptional splicing
| Group Leader | Suyang Zhang |
| Group Site | Zhang Lab |
| Contact | szhangmrclmbacuk |
How RNA transcription and splicing are coordinated in human cells remains a fundamental question in gene regulation. This fully funded PhD position will investigate the molecular architecture of co-transcriptional splicing complexes using cryo-electron microscopy (cryo-EM) and biochemical approaches.
Project description
Accurate gene expression in eukaryotic cells requires tight coordination between transcription and pre-mRNA splicing. During transcription by RNA polymerase II (Pol II), the spliceosome removes introns from nascent RNAs co-transcriptionally. How the transcription and splicing machineries communicate to ensure efficient and accurate splicing remains a fundamental biological question.
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.
Funding and start date
This is a fully funded PhD position within the LMB international PhD Programme, starting in October 2026. The PhD degree will be awarded by the University of Cambridge.
Candidate profile
We are looking for a motivated candidate with a strong interest in molecular biology and structural biology. Applicants should expect to obtain a degree in biology, biochemistry, or a related field by September 2026. International applicants are welcome. Prior lab experience in molecular biology, protein biochemistry, or structural biology is desirable but not required.
Application
To apply for this position, please send your CV, a statement of interest and contact details of two references directly to szhangmrclmbacuk
Applications will be reviewed on a rolling basis.
Application deadline: 14.04.2026