Biology subjects

Seki, Y.

Publications and source records attributed to Seki, Y..

5 recordsLinked to original sources

bioRxiv2025

Genetic background and transient prenatal disruption of vitamin A signaling determine susceptibility to airway hyperresponsiveness in mice

Airway structural changes and hyperresponsiveness (AHR), hallmarks of asthma, are crucially influenced by genetic variations and adverse exposures. While intrauterine environmental perturbations leading to dysfunctional lung development have been linked to adult pulmonary disease, still little is known about the developmental events leading to these postnatal abnormalities. Here, we provide evidence of genetic background playing a key role in this process. Using A/J and C57BL/6J mice known for their distinct susceptibility to AHR, we show that A/J but not C57BL/6J develop an aberrant airway smooth muscle (SM) program and AHR in adulthood when exposed transiently to a vitamin A/retinoic acid (RA)-disrupted intrauterine environment in vivo by a maternal BMS493 administration. Single nuclei multiomics analysis identified a subpopulation of mesenchymal cells that overactivated TGF{beta} targets in response to BMS selectively in A/J, but not C57BL/6J, embryonic lungs. These cells, localized to sites of airway SM initiation, exhibited robust BMS-mediated upregulation of SMAD2/3 targets, including regulators of SM program Pdgfra and Tnc, and showed stable cell proportions despite the marked transcriptional rewiring following RA disruption. These findings identify TGF{beta}-activating mesenchymal cells as a critical niche responsive to RA signaling and reveal how genetic background determines developmental susceptibility to micronutrient perturbations with long-term impact on airway function.

developmental biology↗

bioRxiv2025

dif-XerCD is required for chromosome segregation during cSDR-dependent growth in E. coli

Escherichia coli cells can grow in a DnaA- and oriC-independent manner in rnhA-deficient cells that lack the major RNaseH activity. This mode of replication is named cSDR (constitutive Stable DNA Replication) and is believed to initiate from the sites of RNA-DNA hybrids, although the detailed mechanisms of cSDR are unclear. In this study, we discovered that dif sequence and XerC/D are essential for cSDR-dependent growth. cSDR was observed in either dif or xerC/D mutant cells as efficiently as in the control cells, as measured by the incorporation of [3H]-thymine. However, we found that these mutants accumulate cells with extra DNA contents in the presence of rifampicin and cephalexin, suggesting accumulation of unresolved dimeric or multimeric chromosomes or that of catenated chromosomes due to potential problems in resolution of the replicated chromosomes or in decatenation process. These results indicate that site-specific recombination mediated by dif-XerC/D is essential for cSDR-dependent growth.

molecular biology↗

bioRxiv2024

The disruption of CtBP regulates DUX-dependent and -independent genetic program for the 2-cell-like state in murine embryonic stem cells

After fertilization, maternally deposited mRNA is cleared, and de novo mRNA is transcribed from the zygotic genome through zygotic genome activation (ZGA), a process known as maternal-to-zygotic transition (MZT) occurring in the mouse at 2-cell (2C) stage. 2C-like cells (2CLCs) marked by MERVL expression are transcriptionally similar to 2C embryos spontaneously emerge from mouse embryonic stem cells (mESCs). Although the emergence of 2CLCs completely depends on DUX function, a recent knockout study clearly showed that DUX is dispensable for mouse embryos, suggesting that DUX-independent molecular pathways are not recapitulated in 2CLCs. We present here that the disruption of C-terminal binding protein 1/2 (Ctbp1/2) activates DUX-dependent and -independent molecular pathway associated with the development of early mouse embryos mediated by the upregulation of Preferentially expressed antigen of melanoma family-like 7 (PRAMEL7). Furthermore, the abnormality of the gene expression profile caused by Dux KO is partially rescued by the overexpression of PRAMEL7 in mESCs. Our study provides new insights into the DUX-independent molecular pathway for the activation of early embryonic genes in mESCs.

cell biology↗

bioRxiv2019

Efficient horizontal transmission without viral super-spreaders may cause the high prevalence of STLV-1 infection in Japanese macaques

AbstractsSimian T-cell leukemia virus type-1 (STLV-1) is disseminated among various non-human primate species and is closely related to human T-cell leukemia virus type-1 (HTLV-1), the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Notably, the prevalence of STLV-1 infection in Japanese macaques (JMs) is estimated to be much greater than that in other non-human primates; however, the mechanism and mode of STLV-1 transmission remain unknown. We hypothesized that a substantial proportion of infected macaques may play a critical role as viral super-spreaders for efficient inter-individual transmission leading to the high prevalence of infection. To address this, we examined a cohort of 280 JMs reared in a free-range facility for levels of anti-STLV-1 antibody titers (ABTs) and STLV-1 proviral loads (PVLs). We found that the prevalence of STLV-1 in the cohort reached up to 65% (180/280), however, the ABTs and PVLs were normally distributed with mean values of 4076 and 0.62%, respectively, which were comparable to those of HTLV-1-infected humans. Contrary to our expectations, we did not observe the macaques with abnormally high PVLs and poor ABTs, and therefore, the possibility of viral super-spreaders was unlikely. Results from further analyses regarding age-dependent changes in STLV-1 prevalence and a longitudinal follow-up of STLV-1 seroconversion strongly suggest that frequent horizontal transmission is a major route of STLV-1 infection, probably due to the unique social ecology of JMs associated with environmental adaptation.\n\nImportanceWe investigated the cause of the high prevalence of STLV-1 infection in the studied JMs cohort. Contrary to our expectations, the potential viral super-spreaders as shown by abnormally high PVLs and poor ABTs were not observed among the JMs. Rather, the ABTs and PVLs among the infected JMs were comparable to those of HTLV-1-infected humans although the prevalence of HTLV-1 in humans is much less than the macaques. Further analyses demonstrate that the prevalence drastically increased over one year of age and most of these animals over 6 years of age were infected with STLV-1, and that in the longitudinal follow-up study frequent seroconversion occurred in not only infants but also in juvenile and adult seronegative monkeys (around 20% per year). This is the first report showing that frequent horizontal transmission without viral super-spreaders may cause high prevalence of STLV-1 infection in JMs.

microbiology↗

bioRxiv2018

CD36hi monocytes play immunoregulatory roles in human umbilical cord blood

The fetal and neonatal immune systems are uniquely poised to generate tolerance to self, maternal, and environmental antigens encountered in the womb and shortly after birth. The tolerogenic nature of fetal and neonatal immunity is a rising health concern with the spread of vertically transmitted viruses, such as the Zika virus. A variety of mechanisms contribute to fetal and neonatal tolerance, including a propensity to generate Foxp3+ regulatory T cells (Tregs). Here, we demonstrate that a subset of CD14+ monocytes expressing the scavenger molecule, CD36, is able to generate CD4+ and CD8+ T cells that express Foxp3 from umbilical cord blood (UCB). Monocyte-induced Foxp3+ T cells have potent suppressive functions on T cell proliferation and maintain Foxp3 expression over six weeks in vitro. Importantly, UCB-derived Foxp3+ T cells are distinguishable from adult peripheral blood (APB) CD4+CD25+ Tregs by surface antigen expression. While UCB-derived Foxp3+ T cells express prototypic Treg-associated surface antigens, such as CD25 and glucocorticoid-induced tumor necrosis factor-related receptor (GITR), only UCB-derived Foxp3+ T cells express CD26. In addition, most UCB-derived CD8+Foxp3+ T cells express CD31. Mechanistically, both APB and UCB-derived monocytes support the development of Foxp3+ T cells from naive T cells, but APB naive T cells are less efficient in expressing Foxp3 than UCB naive T cells. These data suggest that antigen presentation by CD36hi monocytes in the fetus leads to the development of a group of T cells that share some but not all phenotypes of adult thymus-derived Tregs.

immunology↗