Biology subjects

Mishima, K.

Publications and source records attributed to Mishima, K..

4 recordsLinked to original sources

bioRxiv2026

Chromosomal evolution and speciation inferred from chromosome-scale genome assemblies in three Cupressaceae species

Chromosome-scale genome assemblies in gymnosperms have lagged behind those of angiosperms, likely due to their large genomes. Coniferous tree species, which belong to the gymnosperms, are important resources for wood production in the forestry industry. To elucidate the evolution and speciation of these species and establish genome resources for breeding, we integrated draft assemblies with optical and genetic mapping to construct chromosome-scale genomes for Japanese cypress (Chamaecyparis obtusa, 8.7 Gb), Japanese cedar (Cryptomeria japonica, 9.6 Gb), and Chinese fir (Cunninghamia lanceolata, 13.4 Gb). Additionally, we assembled and annotated their chloroplast and mitochondrial genomes. Comparative analysis of the nuclear genomes revealed that while synteny is largely conserved, distinct translocations and inversions occurred in chromosomes 2, 6, and 9. Notably, the significantly larger genome of C. lanceolata was associated with frequent tandem gene duplications rather than transposon expansion. These findings suggest that chromosomal rearrangements and segmental duplications played key roles in the divergence of these species. The genomic resources presented here including chromosome-scale sequences, gene annotations, and genetic maps will facilitate advanced conifer genetics and accelerate forest tree breeding programs.

genomics↗

bioRxiv2025

Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated Cachexia

ZIP14/SLC39A14, a membrane-bound metal transporter, is essential for systemic metal homeostasis and has been implicated in inflammatory and metabolic disorders, including cancer-associated cachexia. Despite its biological and therapeutic significance, no selective inhibitors have been identified. Here, we identify 1-phenyl-8-(2-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (PPTD) as the first selective small-molecule inhibitor of ZIP14. PPTD efficiently blocks ZIP14-mediated uptake of zinc, iron, manganese, and cadmium, while sparing the closely related transporter ZIP8/SLC39A8. Mechanistically, PPTD binds specifically to a pocket formed at the dimer interface of ZIP14, as revealed by AlphaFold3 structural prediction, ligand-interaction profiling, structure-activity analyses, and site-directed mutagenesis, providing direct evidence for a targeted inhibition mechanism. ZIP14-driven metal influx promotes reactive oxygen species and lipid peroxidation, leading to cytotoxicity, which PPTD effectively reverses. In vivo, PPTD ameliorates major features of cancer cachexia in mice, including weight loss, reduced survival, muscle wasting, impaired locomotor activity, and disease progression. PPTD thus provides both a chemical probe to dissect ZIP14 function and a potential therapeutic candidate for cancer cachexia, establishing a foundation for the development of therapies targeting ZIP14-mediated metal dysregulation.

biochemistry↗

bioRxiv2023

Generation of salivary glands derived from pluripotent stem cells via conditional blastocyst complementation

Various patients suffer from dry mouth due to salivary gland dysfunction. Whole salivary gland generation and transplantation is a potential therapy to resolve this issue. However, the lineage permissible to design the entire salivary gland generation has been enigmatic. Here, we discovered Foxa2 as a lineage critical for generating a salivary gland via conditional blastocyst complementation (CBC). Foxa2 linage, but not Shh nor Pitx2, initiated to label between the boundary region of the endodermal and the ectodermal oral mucosa before primordial salivary gland formation, resulting in marking the entire salivary gland. The salivary gland was agenesis by depleting Fgfr2 under the Foxa2 lineage in the mice. We rescued this phenotype by injecting donor pluripotent stem cells into the mouse blastocysts. Those mice survived until adulthood with normal salivary glands compatible in size compared with littermate controls. These results indicated that CBC-based salivary gland generation is promising for next-generation cell-based therapy.

developmental biology↗

bioRxiv2022

Haplotype-resolved de novo genome assemblies of four coniferous tree species

Coniferous trees in gymnosperm are an important source of wood production. Because of their long lifecycle, the breeding programs of coniferous tree are time- and labor-consuming. Genomics could accelerate the selection of superior trees or clones in the breeding programs; however, the genomes of coniferous trees are generally giant in size and exhibit high heterozygosity. Therefore, the generation of long contiguous genome assemblies of coniferous species has been difficult. In this study, we optimized the DNA library preparation protocols and employed high-fidelity (HiFi) long-read sequencing technology to sequence and assemble the genomes of four coniferous tree species, Larix kaempferi, Chamaecyparis obtusa, Cryptomeria japonica, and Cunninghamia lanceolata. Genome assemblies of the four species totaled 13.5 Gb (L. kaempferi), 8.5 Gb (C. obtusa), 9.2 Gb (C. japonica), and 11.7 Gb (C. lanceolata), which covered 99.6% of the estimated genome sizes on average. The contig N50 value, which indicates assembly contiguity, ranged from 1.2 Mb in C. obtusa to 16.0 Mb in L. kaempferi, and the assembled sequences contained, on average, 89.2% of the single-copy orthologs conserved in embryophytes. Assembled sequences representing alternative haplotypes covered 70.3-95.1% of the genomes, suggesting that the four coniferous tree genomes exhibit high heterozygosity levels. The genome sequence information obtained in this study represents a milestone in tree genetics and genomics, and will facilitate gene discovery, allele mining, phylogenetics, and evolutionary studies in coniferous trees, and accelerate forest tree breeding programs.

genomics↗