Sugimoto Lab

We aim to understand how the human body and cells sense the availability of oxygen and nutrients, and how dysregulation leads to disease and ageing. We are addressing these fundamental questions by integrating state-of-the-art high-throughput sequencing, proteomics, super-resolution imaging, biochemistry, single-cell and spatial analysis, and computation.   

The human body dynamically adapts to changes in its environment. Cells sense the availability of molecules essential for their survival, such as oxygen and nutrients. We are seeking to understand the molecular basis. Our current focus is on understanding how changes in oxygen availability dynamically control different forms of cellular compartments, such as organelles (e.g. mitochondria and ER), liquid-liquid phase separated molecular condensates and higher order protein-RNA complexes, to mediate physiological responses. To this end, we resolve molecular actions with unprecedented resolution using integrative approaches of experimental and computational techniques. 

Given their fundamental importance in maintaining oxygen and energy homeostasis, dysregulation of these mechanisms is associated with many diseases, including cancer, neurodegenerative disorders, viral infections and ageing. We are also seeking to apply our findings to the treatment and prevention of these conditions.

References

<sup>1. Prange-Barczynska*, Jones*, Sugimoto* et al., Journal of Clinical Investigation, 2024 | * co-first
2. Sugimoto and Ratcliffe, Nature Structural & Molecular Biology, 2022
3. Cockman et al., Proceedings of the National Academy of Sciences, 2022
4. Sugimoto et al., Genome Biology, 2012
5. Sugimoto et al., Nature, 2015
6. Sugimoto et al., Nature Protocols, 2017</sup>
 

Oxygen-dependent regulation of mRNA translation

The efficiency of mRNA translation has a direct effect on protein abundance. Hypoxia (reduced oxygen availability) dynamically affects translational efficiency in a global and gene-specific manner. However, how oxygen availability is transduced to mRNA translational efficiency remains to be understood. We have uncovered the interplay of two major oxygen-sensitive pathways in the regulation of mRNA translation (Sugimoto and Ratcliffe, Nat Struct Mol Biol., 2022). We are currently working to elucidate new mechanisms that mediate key physiological responses through the control of mRNA translation.

Oxygen-dependent regulation of phase-separated condensates

Recent studies have highlighted the critical role of liquid-liquid phase separated molecular condensates in the regulation of gene expression and cell metabolism. Molecular condensates are typically formed by protein-RNA and RNA-RNA interactions (Sugimoto et. al., Nature 2015). Molecular condensates function as a compartment in the cell similar to organelles, but their organisation is highly dynamic. We are investigating the molecular mechanisms by which the cell dynamically forms/dissolves molecular condensates upon changes in oxygen availability with analysing oxygen-dependent post-translational modifications of proteins at unprecedented resolution (Cockman et al., PNAS, 2022). Furthermore, we study how these molecular condensates are perturbed by ageing and diseases that disrupt oxygen delivery (e.g. ischaemic diseases, cancer, neurodegenerative diseases and viral infections).

The role of mitochondria in oxygen sensing

We seek to understand the mechanisms that confer oxygen sensitivity to mitochondria, with a particular focus on the regulation of mitochondrial turnover (also known as mitophagy). We are also investigating how the dysregulation promotes mitochondrial genomic instability and dysfunction, leading to ageing and disease.

New technologies

We are tackling fundamental and challenging biological questions. To this end, we have developed numerous new technologies that shed light on a new aspect of biological systems. The new technologies from us include:

• Spatially resolved and/or single cell analysis of cells and mitochondria, in tissues
• HP5 (to comprehensively and quantitatively study mRNA translation) (Sugimoto and Ratcliffe, Nat Struct Mol Biol., 2022)
• hiCLIP (to comprehensively study RNA-RNA interactions recognised by an RNA binding protein in the cell) (Sugimoto et al, Nature, 2015)
• Computational tools
  • Quantitative analysis of protein modifications using proteomics (Cockman et al., PNAS, 2022)
  • Nucleotide-resolution identifications of protein-binding sites of RNA using CLIP-Seq and iCLIP (Sugimoto et al., Genome Biol. 2012)

We are also currently working on the following technologies:
Live analysis
We have established methods to study organelle turnover (autophagy) and small molecule signalling in response to changes in oxygen availability.

Imaging
We are developing methods to overcome the diffraction barrier of light microscopy to resolve nanoscale structural changes of molecular condensates and organelles.

Single cell and spatial multicomics analysis
We have invented single-cell and spatial multiomics analysis methods to gain deeper insights on cellular states than widely used approaches.

Induced pluripotent stem cells (iPSC)
We use iPSC models to understand oxygen sensing mechanisms in highly oxygen-sensitive tissues.