Biology subjects

Moro, K.

Publications and source records attributed to Moro, K..

3 recordsLinked to original sources

bioRxiv2023

NFκB nuclear dynamics orchestrate inflammatory aging

Upregulation of nuclear factor {kappa}B (NF{kappa}B) signaling is a hallmark of aging and major cause of age-related chronic inflammation; however, its physiological functions and mechanisms remain unclear. By combining mathematical modeling and experiments, we show that dysfunction of negative feedback regulators of NF{kappa}B, I{kappa}B and A20, alters the NF{kappa}B nuclear dynamics from oscillatory to sustained, promoting cellular senescence by remodeling epigenetic regulation and metabolic landscape. Sustained NF{kappa}B activity by I{kappa}B downregulation enhanced inflammation- and senescence-associated gene expression through increased NF{kappa}B-DNA binding and slowed the cell cycle by upregulating purine catabolism via mTORC2/AKT pathways. Notably, I{kappa}B knockdown combined with A20 overexpression resulted in lower NF{kappa}B amplitude, cytokine expression, and SA-{beta}-gal activity than I{kappa}B knockdown alone. I{kappa}B downregulation is correlated with hypoxanthine phosphoribosyltransferase 1 (HPRT1) expression in the purine salvage pathway in aged mouse hearts. Our study suggests that nuclear NF{kappa}B homeostasis is critical for balancing purine metabolism associated with chronic inflammation and tissue aging.

systems biology↗

bioRxiv2023

Identification of a novel enhancer essential for Satb1 expression in TH2 cells and activated ILC2s.

The genome organizer, special AT-rich binding protein-1 (SATB1) functions to globally regulate gene networks during primary T cells development and plays a pivotal role in lineage-specification in CD4+ helper-, CD8+ cytotoxic- and FOXP3+ regulatory-T cell subsets. However, it remains unclear how Satb1 gene expression is controlled, particularly in effector T cell function. Here, by using a novel reporter mouse strain expressing SATB1-Venus and genome editing, we have identified a cis-regulatory enhancer, essential for maintaining Satb1 expression specifically in TH2 cells. This enhancer is occupied by STAT6 and interacts with Satb1 promoters through chromatin looping in TH2 cells. Reduction of Satb1 expression, by the lack of this enhancer, resulted in elevated IL-5 expression in TH2 cells. In addition, we found that Satb1 is induced in activated group 2 innate lymphoid cells (ILC2s) through this enhancer. Collectively, these results provide novel insights into how Satb1 expression is regulated in TH2 cells and ILC2s during type 2 immune responses.

immunology↗

bioRxiv2022

Quantitative live-cell imaging of secretion activity reveals dynamic immune responses

The measurement of cytokine secretions has contributed to the development of immunology; however, new methods that enable highly sensitive and efficient analysis are required for the precise characterisation of dynamic secretion activity when using rare cells or limited human specimens. Here, we report a new technology for quantitative live-cell imaging of secretion activity (qLCI-S), that enables high-throughput and dual-colour detection of prolonged secretion activity at the single-cell level, followed by transcriptome analysis for individual cells based on their phenotype. The power of the qLCI-S was demonstrated by visualising the individual and longitudinal cytokine secretion patterns of group 2 innate lymphoid cells, which comprised <0.01% human peripheral blood mononuclear cells, and identifying their minor subpopulations. This new technology will provide new insights into the spatiotemporal dynamic nature of various secretory functions and the development of fundamental tools for phenotypic drug discovery and regenerative and precision medicine.

biophysics↗