1: Elucidating a New Role for "ATRX Aggregates" in Determining Neural Progenitor Cell Fate / 2: Diverse Manifestations of Sjögren's Disease Caused by Differences in Autoantibodies — Elucidating Pathogenesis through Single-Cell and Spatial Analysis —
Science of the Month - November 2025
1: Elucidating a New Role for "ATRX Aggregates" in Determining Neural Progenitor Cell Fate
Nature Communications.
Ryo Tomooka, Tsukasa Sanosaka, Tamami Miyagi, Tomoko Andoh-Noda, Satoe Banno, Noriko Mizota, Kohsuke Kanekura, Hideyuki Okano, Jun Kohyama
Many mysteries remain regarding the mechanisms of brain development and how neurons are born. In this study, we discovered that ATRX, known as a cause of ATR-X syndrome (which presents with intellectual disability), uses a phenomenon called "liquid-liquid phase separation (LLPS)" to create small droplet-like structures (aggregates) within the nucleus to regulate the expression of genes involved in neuronal differentiation.
While ATRX was previously known as a transcriptional repressor, we found that it also acts as a transcriptional activator through these aggregates. In particular, a polyglutamic acid sequence in a portion of the ATRX protein is crucial for this aggregate formation. It was revealed that in cells where mutations lacking this sequence were introduced, neurons were not sufficiently produced, and abnormalities occurred in the structural formation of the brain.
These results clarify that ATRX determines the fate of neurons not just by acting as a simple genetic switch, but by creating a molecular "field" within the nucleus. This achievement demonstrates that the phase separation phenomenon of proteins is the key to precisely controlling human neural development. Mutations in the ATRX gene have been reported in connection with brain tumors as well as neurodevelopmental issues, and future research is expected to lead to an understanding of developmental disorders and brain tumors, as well as the development of new treatments.
(Jun Kohyama, Faculty of Human Sciences, Waseda University)
2: Diverse Manifestations of Sjögren's Disease Caused by Differences in Autoantibodies — Elucidating Pathogenesis through Single-Cell and Spatial Analysis —
Nature Communications.
Inamo, J., Takeshita, M., Suzuki, K. et al.
Sjögren's disease is an autoimmune disorder that makes it difficult to produce tears and saliva. While it is known that some symptoms vary depending on the type of autoantibodies a patient possesses, the cause of this has not been fully elucidated. In this study, we used cutting-edge "single-cell analysis" and "spatial transcriptomics" to examine the function of each individual cell composing the salivary glands in detail, investigating the commonalities and differences in Sjögren's disease among patients with different autoantibodies. As a result, we found that in all types of patients, "GZMB-positive CD8 T cells" that directly attack the salivary glands and "Tph cells" that assist in antibody production were increased. However, the molecular mechanisms causing inflammation differed depending on the type of autoantibody. In anti-SSA antibody-positive cases, the interferon pathway involved in viral response was active, while in anti-centromere antibody-positive cases, the TGF-β pathway promoting fibrosis was active. Furthermore, we identified "THY1-positive fibroblasts" as cells located at the center of inflammation that direct the immune response. These findings pave the way for personalized medicine tailored to the specific pathology of each patient and are expected to lead to the development of new treatments to replace conventional symptomatic therapies.
(Masaru Takeshita, Department of Rheumatology and Systemic Rheumatic Diseases)
Other Published Papers
1: Trajectories of Angina After Initial Invasive vs Conservative Strategy for Chronic Coronary Disease.
Journal of the American College of Cardiology.
Nobuhiro Ikemura, Philip G. Jones, Zhuxuan Fu, Paul S. Chan, Charles F. Sherrod, IV, Suzanne V. Arnold, David J. Cohen, Daniel B. Mark, David J. Maron, Judith S. Hochman, and John A. Spertus ISCHEMIA Research Group