Sugimoto Lab

The human body adapts to varying environments. For this, the cells sense the availability of molecules crucial for their survival, such as oxygen and nutrients. We are particularly interested in the molecular basis of rapid oxygen sensing. Due to the critical importance of oxygen to life, the cell must rapidly respond to the changes in oxygen availability. However, the molecular mechanisms largely remain to be understood. 

Our current focus is to understand the roles of RNA in rapid oxygen sensing¹. RNA acts as the carrier of the genetic information of a gene, and the information is used to synthesize “the functional product”, protein. However, during its life cycle, RNA dynamically interacts with other molecules and RNA can even form a large compartment through phase separation in the cell. The interaction of RNA and other molecules affects not only the synthesis rate of the encoded protein, but also many other functions of the cells.  We are investigating how the availability of oxygen controls these RNA-mediated processes^{2, 3}. 

We are developing innovative high-throughput technologies that can comprehensively measure the interactions and regulatory status of key biological molecules (e.g. RNA and protein), and are employing data science to make sense of the complex data sets^{2, 4-6}.   

We are also interested in applying our findings to treat diseases such as cancer, neurodegenerative diseases, and viral infections². 

<sup>1. Prange-Barczynska et al., bioRxiv, 2023
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

Translational efficiency of mRNA is a key determinant of the expression level of genes. Hypoxia (a decreased oxygen availability) dynamically affects translational efficiency in a global and gene specific manner. Yet, how oxygen availability is transduced to the translational efficiency of mRNA remain to be understood. We have provided key insights on this (Sugimoto and Ratcliffe, Nat Struct Mol Biol., 2022), and working to pinpoint the exact mechanisms.

Oxygen-dependent regulation of phase-separated condensates

Recent studies have underscored a crucial role of molecular condensates in the regulation of gene expression and the cell metabolism. The condensates are typically formed by protein-RNA interactions and work as a compartment in the cell, similar to organelles. We are investigating the molecular mechanisms by which the cell dynamically forms/dissolves molecular condensates upon changes in oxygen availability (Cockman et al., PNAS, 2022).

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:

• 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:
Imaging
We are investigating how oxygen availability affects different compartments of the cell using high-resolution/high-throughput imaging analysis.

Induced pluripotent stem cell (iPSC)
In order to understand the oxygen sensing mechanisms in highly oxygen sensitive tissues, we are employing iPSC models.