Exploring the mRNA translation in embryonic development, aging, and disease
Dr. Fujii’s research is centered on understanding of the gene regulation focusing on the step of mRNA translation. Our research program will unravel new layers of spatiotemporal specificity and fidelity of protein synthesis, to further understand the impact of translational regulation in development and in diseases, particularly those caused by protein aggregation such as neurodegenerative disorders.
1. How to build up functional proteome?
Proteins are the building blocks of our bodies that provide cell type specific functions. A key factor in ensuring human health and longevity is the homeostasis of proteins. Indeed, loss of proteostasis is a hallmark of aging and neurological diseases. To maintain functional protein synthesis, eukaryotic cells have a quality control system eliminating non-functional ribosomes that cannot produce protein [Fujii et al. Genes Dev 2009, EMBO.J 2012]. However, the protein production step, mRNA translation, is highly error-prone to amino acid misincorporation, stop codon readthrough, and ribosomal frameshifting. By focusing on the ribosome, we found a molecular mechanism to increase accuracy of ribosomal decoding in eukaryotes beyond prokaryotes [Fujii et al. Mol Cell 2018]. We further seek to understand the dynamics of such regulation in mammalian organisms and how regulation contributes to our health.
- What are the dynamics of translation fidelity between tissues during mammalian development, across aging, and in disease?
- What is the molecular mechanism that regulates the accuracy of ribosomal decoding?
- How can we make ribosomes more accurate?
2. Decoding the role of mRNA translation in cell signaling
A key factor for the spatiotemporal queue in developing embryos is developmental cell signaling which allows each cell to “know” where they are and what to become. However, all cell signaling has been used multiple times during embryonic development in different contexts and how signaling is specialized for each specific context is still not well understood. Although mRNA translation has always been thought of as in the “on” state, we found that translation of important developmental signaling circuitry including Shh, Wnt, and Hippo signaling are highly repressed and differentially regulated between tissues [Fujii et al. Nat Commun 2017]. We want to mechanistically understand how translational regulation of signaling transcripts impacts on tissue-specific signaling and species-specific tissue patterning.
- What are the cis-regulatory elements and trans-acting factors that regulate the translation of signaling transcripts?
- What is the trigger to turn “on” the translation of signaling transcripts?
- What is the impact of translation regulation on tissue specific cell signaling and species-specific tissue patterning?
We approach these outstanding questions using a variety of model systems such as mouse, cultured cell, and yeast and apply state-of-the-art Biochemistry, Genetics, and Genomics to decode the impact of translation regulation in mammalian development and homeostasis at a molecular level.
Fujii, K., Susanto, TT., Saurabh, S., and Barna, M. Decoding the function of expansion segments in ribosomes. Molecular Cell 72, 1013-1020 (2018) DOI: 10.1016/j.molcel.2018.11.023
＊Shi, Z., ＊Fujii, K., Kovary, K.M., Genuth, N.R., Röst, H.L., Teruel, M.N., and Barna, M. Heterogeneous ribosomes preferentially translate distinct subpools of mRNAs genome-wide. Molecular Cell 67, 71-83 (2017) ＊co-first author DOI: 10.1016/j.molcel.2017.05.021
＊Fujii, K., ＊Shi, Z., ＊Zhulyn, O., Denans, N., and Barna, M. Pervasive translational regulation of the cell signaling circuitry underlies mammalian development. Nature Communications 8, 14443 (2017) ＊co-first author DOI: 10.1038/ncomms14443
＊Fujii, K., ＊Kitabatake, M., Sakata, T., and Ohno, M. 40S subunit dissociation and proteasome-dependent RNA degradation in non-functional 25S rRNA decay. The EMBO Journal 31, 2579-2589 (2012) ＊co-first author DOI: 10.1038/emboj.2012.85
＊Fujii, K., ＊Kitabatake, M., Sakata, T., Miyata, A., and Ohno, M. A role for ubiquitin in the clearance of nonfunctional rRNAs. Genes & Development 23, 963-974 (2009) ＊co-first author DOI: 10.1101/gad.1775609
Honors & Awards
Poster Award 1st Place, The Bay Area RNA Club, 2017
Long Term Fellow, Human Frontier Science Program (HFSP), 2013-2016
Postdoctoral fellowship, The Uehara Memorial Foundation, 2012-2013
Research fellowship for young scientists, Japan Society for the Promotion of Science (JSPS), 2010-2012
Return exemption of scholarship due to outstanding achievements, Japan Student Services Organization (JASSO), 2010
Poster Award 2nd Place, 16th East Asia Joint Conference on Biomedical Research, 2009
Postdoctoral Fellow, Stanford University
Ph.D. Kyoto University
M.S. Kyoto University
B.S. Tohoku University