Research

RNA regulation in mammalian brain development and disease

Nonsense-mediated mRNA decay in brain development

Nonsense-mediated mRNA decay (NMD) is a conserved RNA surveillance mechanism that selectively degrades aberrant and physiological transcripts. Our research has revealed critical roles for NMD in brain development. We demonstrated a link between NMD dysfunction and microcephaly (Lin^#, Zhao^#, Kubota et al., Neuron, 2024). Building on this, we showed that loss of UPF2, a core NMD factor, delays neuronal migration and disrupts cortical lamination, with transcriptomic analyses uncovering NMD-mediated regulation of Reelin signaling, microtubule dynamics, and ciliary gene networks (Lin^#, Kubota^# et al., Cell Reports, 2026).

Fig_Lin2026_1
Lin^#, Kubota^# et al, Cell Reports 45(3), 117027, 2026.

Alternative RNA splicing in neural and glial cell identity

Alternative RNA splicing plays an essential role in establishing cell type identity in the brain. RNA-binding protein PTBP1 has been proposed as a master regulator of astrocyte-to-neuron conversion, but its precise role remained unclear. We investigated the effects of PTBP1 depletion in mature astrocytes and found that while it induces distinct splicing alterations, it does not trigger neuronal gene programs, challenging the prevailing model of PTBP1-mediated cell fate conversion (Zhang^#, Kubota^#, Nikom^# et al., eLife, 2025).

Software development for systematic identification of differential RNA splicing

Shiba: a versatile computational method for systematic identification of differential RNA splicing

Alternative RNA splicing is a fundamental regulatory process that generates transcript diversity and cell type variation. Several computational tools have been developed to analyze AS from RNA-seq data, but they are often limited by the high false-positive rate and low reproducibility. I have developed a versatile computational method, called Shiba, that enables systematic identification of differential RNA splicing across platforms, bulk and single-cell RNA-seq data (Kubota et al., Nucleic Acids Research, 2025).

Fig_Kubota2025_1

Fig_Kubota2024_2
Kubota et al, Nucleic Acids Research 53(4), 2025, gkaf098.

Alternative RNA splicing events identified in Shiba can be visualized by shiba2sashimi, a utility to create Sashimi plots.

Sashimi plot example

Mapping of functional genomic variants in human disease risk

It has been largely unknown which and how genomic variants affect gene expression level and human disease risk. Previously I have worked on developing computational methods for identifying functional variants in the human genome.