Nuclear Architecture, Biomolecular Condensates & Gene Regulation

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Nuclear architecture and 3D genomic organisation exert profound effects on gene expression. While intra- and interchromosomal interactions can amplify transcription via enhancers and super-enhancers, the spatial integration of transcription and splicing can facilitate RNA processing.

The study of biomolecular condensates has shifted the paradigm of cellular organisation, yet their role in parasitic biology remains understudied. By acting as reaction hubs, these condensates either sequester factors to silence genes or concentrate enzymes (up to 100x) to accelerate metabolic and transcriptional processes.

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Kinetoplastid Parasites: A Window into Extreme Biology

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Trypanosoma brucei and Leishmania parasites offer a unique lens through which to explore the functional limits of spatial regulation. These protozoa organise genes into long polycistronic clusters and lack conventional Pol-II promoters or enhancers. With negligible control over transcription initiation, gene expression is regulated primarily through post-transcriptional RNA processing and stability.

For instance, to evade host immunity, T. brucei employs extreme biological solutions to express a single Variant Surface Glycoprotein (VSG) from a vast repertoire. They assemble a specialised nuclear body - the Expression Site Body (ESB) - that enables high-rate Pol-I transcription of mRNA (the only known eukaryote to do it). This system also couples transcription with spatially regulated decay to fine-tune expression of the active-VSG and other virulence genes, which are co-transcribed within the same transcription-unit. Further, by integrating interchromosomal interactions, unique RNA modifications, and specialised RNA-binding proteins, the parasite ensures unparalleled VSG transcript processing and stability. Consequently, the trypanosome ESB represents an exquisite model for studying gene amplification and selection. 

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Our Research Focus

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Our lab investigates how higher-order chromatin features and nuclear compartmentalisation influence gene expression in T. brucei and Leishmania, focusing on highly expressed virulence genes. Their divergent biology provides a rare opportunity to study the fundamental rules of cellular organisation and the limits of condensate-driven regulation, including the role of PTMs such as phosphorylation and SUMOylation. Our work sheds light on fundamental mechanisms of nuclear organisation, condensate assembly and gene expression regulation while identifying parasite-specific vulnerabilities.

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Technologies

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Genetic Engineering

• CRISPR/Cas9

• RNAi & protein-degron mediated knockdowns

• DiCre recombinase-based systems

Imaging

• Super-resolution fluorescence microscopy: 3D-SIM, UExM, PALM/STORM

• Cryo-EM

Proteomics

• AP-MS and XL-AP-MS

• TurboID & APEX2 PL-MS

• Phosphoproteomics & DiGly Proteomics

Genomics

• RNA-Seq & single-cell RNA-Seq

• Hi-C / Micro-C

• ChIP-Seq, DRIP-Seq, and CLIP-Seq​