Our vision and research
DNA Event Recording BiologyWhile early mammalian embryogenesis can be observed at the single-cell resolution under a microscope, a cell division lineage of whole-body development is yet to be resolved. The continuous turnover and response of cells during homeostasis, as well as in many disorders, also remain unclear. At present, no technology enables efficient analysis of dynamic changes in molecular profiles and cellular behaviors in complex biological systems. The Yachie laboratory is developing “DNA event recording” technologies, by which high-resolution molecular and cellular information of individual cells in a multicellular organism can be progressively stored in cell-embedded synthetic “DNA tapes.” Thus, at the time of observation, such a system allows the readout of historical molecular and cellular information of many cells using high-throughput DNA sequencing. Harnessing genome editing, cell engineering, mouse genetics, and high-performance computing, Dr. Yachie and his research team aim to establish “Sense,” “Write,” “Store,” and “Read” technologies for the massive tracing of molecular and cellular dynamics in high-resolution. A perspective article on DNA event recording from our laboratory: Masuyama N, Konno N & Yachie N. Molecular recorders to track cellular events. Our major research topics include: Development of new genome editing technologies Genome Editing Projects The recent understanding of CRISPR systems has triggered the dramatic development of genome editing technologies. In addition to double-stranded DNA cleavage and nicking, catalytically inactivated Cas9 mutants anchored to functional protein and RNA domains have enabled flexible regulation of gene transcriptions and epigenetic modifications at nearly any sequence complementary to the designed guide RNA. Notably, targeted DNA deamination strategies coupled with CRISPR systems enable targeted C•G to T•A and A•T to G•C modifications. This base editing approach allows direct genomic programming to create more stringent and complex cellular circuits compared to the conventional transcriptional induction systems. As basic techniques continue to enhance various research projects in our group, we are developing new base editors and new frameworks for genetics. Sakata RC, Ishiguro S, Mori H et al. Base editors for simultaneous introduction of C-to-T and A-to-G mutations. Nature Biotechnology 38, 865-869 (2020) PDF Nishida K et al. Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems. Cell Lineage Tracing ProjectsDevelopment of any multicellular organism starts from a single fertilized egg. Individuals and organs are formed through cell divisions and differentiation where a large number of cells and their cellular pathways crosstalk. Based on a belief that a complete information of the cell lineaging pathways to organs and functional cells could be a strong backbone for developmental biology, we are developing a high-resolution cell lineage tracing method using DNA barcodes, genome editing, and single cell technologies, aiming to capture the whole body cell lineage of mammalian development (mammalian reference cell lineage) at nearly single cell division resolution. Konno N et al. Deep distributed computing to reconstruct extremely large lineage trees. Interactome Projects Cancers and many other human diseases are not the product of defects in a few genes, proteins or simple pathways. Instead, they involve a complex web of molecular interactions that are dynamically regulated. Recent studies have demonstrated that the projection of genomic mutations to a reference cellular regulatory network could enhance the performance of disease phenotype prediction and that disease mutations alter more functional protein interactions than the other mutations. Therefore, conditional protein interactome information for different proteoforms (splicing variants and modifications), mutations, individuals and environments would deepen our understanding of collapses in functional networks and enable high precision prediction of disease phenotypes. However, such screening is difficult due to the combinatorial explosion in a number of experiments. Using DNA barcodes, barcode fusion concatenating different information and next-generation DNA sequencing, we are developing experimental frameworks that enable high-throughput screening methods of conditional protein interactions. Yachie N and Petsalaki E et al. Pooled-matrix protein interaction screens using Barcode Fusion Genetics. Bioinformatics ProjectsOur group has various bioinformatics projects which range from supporting experimental projects by producing new types of experimental datasets, establishing new data analysis methods as well as other independent studies in bioinformatics. Our topics include data analysis of DNA barcodes and genome editing spectra, development of a parallel distributed computing method to reconstruct large cell and evolutionary lineages and discovery and analysis of structured and patterned DNA sequence elements in large genomic resources. Mori H et al. Fast and global detection of periodic sequence repeats in large genomic resources. Konno N et al. Deep distributed computing to reconstruct extremely large lineage trees. Other research topics in our group include laboratory automation, DNA data storage and in vitro DNA computing using genome editing. Yachie N, Robotic Biology Consortium & Natsume T. Robotic crowd biology with Maholo LabDroids. Mori H & Yachie N. A framework to efficiently describe and share reproducible DNA materials and construction protocols. Positions AvailableWe are seeking creative and talented postdocs and students. |
