Structural and functional analysis of multi-protein complexes in genome regulation

• PhD
• Honours

DNA activity is tightly controlled, and its integrity is protected to control gene expression and cell fate, without altering the underlying genetic code. Such a level of regulation is achieved through the compaction of DNA into a complex three-dimensional structure in which genes are inactive, known as heterochromatin – the genomic ‘dark matter’ of a cell.

This epigenetic control is crucial for human development and health because it defines the identity and, therefore, the role of every cell in the body. Unsurprisingly, malfunction of these processes leads to cancer, developmental defects, aging, and susceptibility to infectious diseases.

This exciting project will focus on understanding the structural basis of how various multi-protein complexes regulate heterochromatin.

Students will use the insect cell expression system to produce these complexes, followed by in vitro reconstitution of their activities, and then utilise cryo-electron microscopy and mass spectrometry to elucidate the atomic details of them (similar work from the lab: Tan, Nature Communications 2025 16, 5606.

Our laboratory uses a hybrid approach to study the structure and function of multi-protein complexes involved in genome regulation and protection (Tan et al Nature Comms 2025, Shakeel, Rajendra et al Nature 2019; Alcon, Shakeel et al Nature Str Mol Bio 2020, Siljacki et al Nature Str Mol Bio in press).

We in vitro reconstitute activity of these cellular machines to dissect the role of each subunit and built atomic models using single particle cryo-electron microscopy and complementary mass spectrometry methods (native, cross-linking and hydrogen-deuterium exchange). By understanding the structure and mechanisms of these complexes, we will gain insight into the regulation of gene expression and find new targets of intervention when these processes are disrupted.

We are a team of biochemists and structural biologists with 10 years of experience in cryo-electron microscopy and biochemistry.