Biology subjects

Amagai, M.

Publications and source records attributed to Amagai, M..

4 recordsLinked to original sources

bioRxiv2025

Epigenomic and transcriptomic germ-free ageing atlas reveals sterile inflammation as an intrinsic ageing feature

Inflammageing is a hallmark of ageing. Commensal microbiota plays crucial roles in maintaining tissue homeostasis, yet its impact on cellular ageing and inflammageing remains poorly understood. Here we present a comprehensive single-cell epigenomic and transcriptomic atlas of tissues from mice aged under specific pathogen-free (SPF) or germ-free (GF) conditions. Microbiota conferred beneficial effects in young mice but accelerated various ageing features in old, such as age-related AP-1 pathway upregulation, senescence and transcriptomic alterations, likely due to age-associated dysbiosis. Strikingly, inflammatory signatures persisted across cell types in aged GF mouse tissues, establishing sterile inflammation as an intrinsic feature of ageing. Age-associated B cells expanded equally under GF and SPF conditions, raising the possibility that they function as intrinsic, microbiota-independent drivers of inflammageing and potential therapeutic targets. The atlas provides a resource for distinguishing intrinsic ageing features from those modulated by the microbiota, illuminating mechanisms of cellular ageing and potential anti-ageing interventions. HighlightsSterile inflammation and age-associated B cell expansion are prominent intrinsic ageing features The upregulation of age-associated AP-1 pathways and senescence of alveolar macrophages are attenuated in germ-free condition Germ-free condition induces premature ageing-like features in young mouse tissues but delays ageing features in old mice across multiple cell types

genomics↗

bioRxiv2023

A single-cell atlas of transcribed cis-regulatory elements in the human genome

Transcribed cis-regulatory elements (tCREs), such as promoters and enhancers, are fundamental to modulate gene expression and define cell identity. The detailed mapping of tCREs at single-cell resolution is essential for understanding the regulatory mechanisms that govern cellular functions. Prior tCRE catalogs, limited by bulk analysis, have often overlooked cellular heterogeneity. We have constructed a tCRE atlas using single-cell 5-RNA-seq, capturing over 340,000 single-cells from 23 human tissues and annotating more than 175,000 tCREs, substantially enhancing the scope and granularity of existing cis-regulatory element annotations in the human genome. This atlas unveils patterns of gene regulation, revealing connections between broadly expressed promoters and cell type-specific distal tCREs. Assessing trait heritability at single-cell resolution with a novel tCRE module-based approach, we uncovered the nuanced trait-gene regulatory relationships across a continuum of cell populations, offering insights beyond traditional gene-level and bulk-sample analyses. Our study bridges the gap between gene regulation and trait heritability, underscoring the potential of single-cell analysis to elucidate the genetic foundations of complex traits. These insights set the stage for future research to investigate the impact of genetic variations on diseases at the individual level, advancing the understanding of cellular and molecular basis of trait heritability.

genomics↗

bioRxiv2021

Inhibition of immunoglobulin class-switching prevents pemphigus onset in desmoglein 3-specific B cell receptor knock-in mouse

Although immunoglobulin class-switching is essential for humoral immunity, its role in B-cell immune tolerance remains unclear. Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3, an adhesion molecule of keratinocytes. In this study, we generated knock-in mice that express anti-Dsg3 AK23 autoantibodies. Knock-in B cells developed normally in vivo and showed Ca2+ influx upon IgM cross-linking in vitro. The mice predominantly produced circulating AK23 IgM but little IgG antibodies. Although no IgG deposition or blister formation was observed in Dsg3-bearing tissues, Dsg3 immunization forced to induce pemphigus phenotype after class-switching to IgG in vivo. Transcriptomic analysis revealed that FCGR2B and Fc{gamma}RIIB-related genes were downregulated in B cells from peripheral blood of pemphigus patients. Indeed, in AK23 knock-in mice, Fcgr2b deficiency or haploinsufficiency spontaneously led to class-switching, AK23 IgG production, and pemphigus phenotype development. Thus, inhibition of pathogenic class-switching is a crucial tolerogenic process to prevent pemphigus onset, where attenuated Fc{gamma}RIIB signaling is one of the key predispositions to break this tolerogenic state.

immunology↗

bioRxiv2018

The Desmosome is a Mesoscale Lipid Raft-Like Membrane Domain

Desmogleins are cadherin family adhesion molecules essential for epidermal integrity. Previous studies have shown that desmogleins associate with lipid rafts, but the significance of this association was not clear. Here, we report that the desmoglein transmembrane domain (TMD) is the primary determinant of raft association. Further, we identify a novel mutation in the DSG1 TMD (G562R) that causes severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome. Molecular modeling predicts that this G to R mutation shortens the DSG1 TMD, and experiments directly demonstrate that this mutation compromises both lipid raft association and desmosome incorporation. Finally, cryo-electron tomography (cryo-ET) indicates that the lipid bilayer within the desmosome is ~10% thicker than adjacent regions of the plasma membrane. These findings suggest that differences in bilayer thickness influence the organization of adhesion molecules within the epithelial plasma membrane, with cadherin TMDs recruited to the desmosome via establishment of a specialized mesoscale lipid raft-like membrane domain.

cell biology↗