Biology subjects

Honjo, T.

Publications and source records attributed to Honjo, T..

4 recordsLinked to original sources

bioRxiv2026

2'-O-Methylated ncRNA condensates form a recombination center for IgH synapsis

How fibrillarin (FBL), an RNA 2'-O-methyltransferase, regulates antibody diversification remains unclear. This study demonstrated that FBL promotes switch (S)-S DNA synapsis at the IgH locus during class switch recombination (CSR), without affecting DNA cleavage. Both RNA-binding and catalytic activities of FBL were essential for CSR. Moreover, MED19 supported DNA cleavage and synapsis by regulating snoRNAs that guide 2'-O-methylation. Mechanistically, FBL methylated -germline transcripts (-GLTs), cis-acting noncoding RNAs forming nuclear condensates harboring machinery for RNA processing, RNP remodeling, and chromatin dynamics. FBL-mediated 2'-O-methylation governed condensate protein composition. FBL suppression aberrantly enriched nucleolar proteins, including WDR74. Crucially, low WDR74 expression in B cells promoted - and -GLT condensate fusion, thereby enhancing S-S synapsis, CSR, and IgH/c-Myc translocation, potentially contributing to poor myeloma prognosis. Altogether, our findings revealed that RNA 2'-O-methylation dictates GLT condensate composition and fusion dynamics to establish a recombination center, driving genomic DNA synapsis in B cells.

molecular biology↗

bioRxiv2024

PD-1 negatively regulates helper T cell differentiation into Th2

Programmed Cell Death Protein-1 (PD-1) represents endogenous mechanisms of negative immunoregulation. While the modulation of effector functions has been the major focus of PD-1 research, quick PD-1 upregulation in naive T cells starting 1 h after priming raised a possibility that PD-1 also affects the development of effector T cells. The role of PD-1 in functional differentiation into Th1 and Th2 has been unclear. In murine naive CD4+ T cell activation, we found that PD-1 stimulation during the early stage of T cell activation strongly impaired Th2 cell development, while Th1 cell induction was relatively resistant to this immunosuppressive signaling. The steep decline in Th2 cell induction suggested the significance of PD-1 in allergic inflammation. Treatment with anti-human PD-1 agonist antibody inhibited allergic inflammation in human PD-1-knock-in mice as shown by the reduction of Th2 cells, IgE levels and eosinophilic infiltration. This study shows that PD-1 regulates not only the intensity but also the quality of immune response by deviating Th differentiation. PD-1 stimulators are projected to be valuable in suppressing various forms of inflammatory activities, but the efficacy against Th2-dominant immune response may be particularly high.

immunology↗

bioRxiv2022

XLID Syndrome Gene Med12 Promotes Ig Isotype Switching through Chromatin Modification and Enhancer RNA regulation

The transcriptional co-activator Med12 regulates gene expression through the function of its kinase module and by interacting with the larger Mediator complex and associated RNA Polymerase II (RNAPII). Here, we show a kinase module-independent function of Med12 in antibody class switching recombination (CSR). Med12 is essential for IgH 3 regulatory region (3RR) or super-enhancer activation and functions with p300 and Jmjd6/Carm1 coactivator complexes. Med12 deficiency leads to a dramatic decrease in H3K27 acetylation and enhancer RNA (eRNA) transcription at 3RR, with concomitant impairment of AID-induced DNA double strand breaks, long-range S-S synapse formation, and 3RR-E interaction. CRISPR/dCas9-mediated enhancer activation re-establishes the epigenomic and transcriptional hallmarks of the 3RR super-enhancer, fully restoring Med12 depletion defects. Notably, we find that 3RR derived eRNAs are critical for promoting proper S region epigenetic regulation, S-S synapse formation and recruitment of Med12 and AID to the IgH locus. We find specific X-Linked intellectual disability syndrome associated Med12 mutations are defective in both 3RR eRNA transcription and CSR, suggesting B and neuronal cells may have cell-specific super-enhancer dysfunctions. We conclude Med12 is essential for IgH3RR activation and eRNA transcription and plays a central role in AID-induced antibody gene diversification and genomic instability in B cells.

immunology↗

bioRxiv2019

Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy

PD-1 blockade therapy has revolutionized cancer treatments. However, a substantial population of patients is unresponsive. To rescue unresponsive patients, the mechanism of unresponsiveness to PD-1 blockade therapy must be elucidated. Using a bilateral tumor model where responsive and unresponsive tumors were inoculated into different sides of the mouse belly, we demonstrated that unresponsive tumors can be categorized into two groups: with and without systemic immunosuppressive property (SIP). The SIP-positive tumors released uncharacterized, non-proteinaceous small molecules which inhibited T cell proliferation and mitochondrial activation. By contrast, the SIP-negative B16 tumor, escaped from immunity by losing MHC class I expression. Unresponsiveness of SIP-positive tumors was partially overcome by improving the mitochondrial function with a mitochondrial activator; this was not successful to B16, which employs immune ignorance. These results demonstrated that our bilateral tumor model was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop strategy for proper combination therapy.

immunology↗