Biology subjects

Kitaguchi, Y.

Publications and source records attributed to Kitaguchi, Y..

5 recordsLinked to original sources

bioRxiv2026

Circadian temperature compensation is intrinsically linked with metabolism and redox signaling

Circadian rhythms are a universal property of organisms, and a defining property of these oscillators is the ability to maintain a precise period at different temperatures. Indeed, the discovery in the 1950s of this property, known as "temperature compensation," was a watershed event in our understanding of biological timekeeping. Since that time, however, almost no general principles have emerged that uncover the mechanistic basis of how circadian timekeepers defy the rules" of temperature dependence of biochemical reactions. A genetic investigation of circadian temperature compensation revealed that the sensing of metabolism and ensuing modulation of the core mechanism preserves a constant circadian period. Intracellular redox sensing of metabolic rate is intrinsic to this compensation, and this relationship is conserved in bacterial and mammalian cells. These insights explain previously inexplicable observations of the interaction between redox reactions and circadian timekeeping. These results introduce a previously unknown linkage between temperature compensation and metabolism.

cell biology↗

bioRxiv2025

Attractive and repulsive couplings between circadian pacemaker neurons promote entrainment to light-dark cycles with after-effect

The mammalian circadian pacemaker, suprachiasmatic nucleus (SCN), comprises a core region that receives light signals from the retina and a shell region that outputs pacemaking rhythms to peripheral tissues. The free-running period (FRP) of animals in constant darkness (DD) correlates with the period of the preceding LD cycle, a phenomenon known as after-effect. To elucidate the mechanisms underlying robust entrainment and after-effect, we analyzed phase oscillator models incorporating attractive and repulsive couplings that respectively decrease or increase phase differences between oscillators. Attractive coupling from the core to shell regions accounts for experimentally observed phase relationships between these regions under LD cycles. Remarkably, repulsive coupling from the shell to core regions promotes SCN entrainability to LD cycles. Furthermore, after transfer to DD, the FRP slowly returns to the intrinsic SCN period, reflecting the after-effect. Our analysis identifies an SCN coupling architecture that underlies stable daily activity rhythms.

physiology↗

bioRxiv2024

Downregulations of mRNA expressions in the EPAS1and EGLN1: Unraveling a genetic mechanism for high-altitude hypoxia adaptation in Sherpa highlanders

Sherpa highlanders exhibit unique hypoxia-tolerant traits, likely evolved through natural selection in response to high-altitude conditions. Previous research has implicated EPAS1 and EGLN1 in this adaptation, but their functional mechanisms remain unclear. This study aims to elucidate these mechanisms by exploring mRNA expressions of EPAS1 and EGLN1 in Sherpa highlanders. Field investigations enrolled 54 healthy Sherpa highlanders and 25 non-Sherpa lowlanders in Namche Bazaar (3,440 m) and Kathmandu (1,300 m), respectively. Venous blood was collected for erythropoietin (EPO) measurements, EPAS1 and EGLN1 mRNA expression analyses, and genotyping of single nucleotide polymorphisms (SNPs) rs13419896 and rs4953354 in EPAS1, as well as rs1435166 and rs2153364 SNPs in EGLN1. Comparative analyses were conducted on these elements between highlanders and lowlanders. Despite decreased SpO2 in Sherpa highlanders, EPO concentrations did not elevate at high altitudes. The EPAS1 and EGLN1 mRNA expressions were significantly lower in Sherpa highlanders compared to non-Sherpa lowlanders. Moreover, genotype distributions and allele frequencies of rs13419896 and rs4953354 in EPAS1, as well as rs1435166 and rs2153364 in EGLN1, differed significantly between Sherpa highlanders and non-Sherpa lowlanders. Analyses of the relative mRNA expressions of EPAS1 and EGLN1 by the SNPs suggested that the rs13419896/G and rs4953354/A alleles in EPAS1, as well as the rs1435166/G and rs2153364/A alleles in EGLN1, have down-regulatory effects on the gene mRNA expressions in Sherpa highlanders, contributing to inhibiting the EPO hypoxia response and exhibiting hypoxia-tolerant EPO levels in Sherpa highlanders. Natural selection, driven by high-altitude hypoxia, has encouraged adaptive evolution in Sherpa highlanders, including modifications in EPAS1 and EGLN1 genes. This evolutionary process leads to the downregulation of gene mRNA expressions, effectively tempering EPO responses to hypoxia and thereby enabling adaptation to high-altitude environments.

genetics↗

bioRxiv2022

Cell size homeostasis under the circadian regulation of cell division in cyanobacteria

Bacterial cells maintain their characteristic cell size over many generations. Several rodshaped bacteria, such as Escherichia coli and the cyanobacteria Synechococcus elongatus, divide after adding a constant length to their length at birth. Through this division control known as the adder mechanism, perturbation in cell length due to physiological fluctuation decays over generations at a rate of 2-1 per cell division. However, previous experiments have shown that the circadian clock in cyanobacteria reduces cell division frequency at a specific time of day under constant light. This circadian gating should modulate the division control by the adder mechanism, but its significance remains unknown. Here we address how the circadian gating affects cell length, doubling time, and cell length stability in cyanobacteria by using mathematical models. We show that a cell subject to circadian gating grows for a long time, and gives birth to elongated daughter cells. These elongated daughter cells grow faster than the previous generation, as elongation speed is proportional to cell length and divide in a short time before the next gating. Hence, the distributions of doubling time and cell length become bimodal, as observed in experimental data. Interestingly, the average doubling time over the population of cells is independent of gating because the extension of doubling time by gating is compensated by its reduction in the subsequent generation. On the other hand, average cell length is increased by gating, suggesting that the circadian clock controls cell length. We then show that the decay rate of perturbation in cell length depends on the ratio of delay in division by the gating{tau} G to the average doubling time{tau} 0 as 2{tau}G/{tau}0-1. We estimated{tau} G {approx} 2.5,{tau} 0 {approx} 13.6 hours, and{tau} G/{tau}0 {approx} 0.18 from experimental data, indicating that a long doubling time in cyanobacteria maintains the decay rate similar to that of the adder mechanism. Thus, our analysis suggests that the acquisition of the circadian clock during evolution did not impose a constraint on cell size homeostasis in cyanobacteria.

cell biology↗

bioRxiv2020

Hypoxia-tolerant vascular endothelial growth factor-A (VEGF-A) and the genetic variations of VEGFA in Sherpa highlanders

Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, partly by one of the adaptation mechanisms promoting increases of microcirculatory blood flow and capillary density at high altitude for restoring oxygen supply to tissues. Hypoxia stimulates vascular endothelial growth factor (VEGF), which is an important signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Our present study included 51 Sherpas dwelling in Namche Bazaar village (3440 m) and 76 non-Sherpa lowlanders residing in Kathmandu (1300 m) in Nepal. In these participants, we measured plasma VEGF-A concentrations and genotyped five single-nucleotide polymorphisms (SNPs) of VEGFA: rs699947, rs8333061, rs1570360, and rs2010963 in the 5'-untranslated region (5'-UTR); and rs3025039 in the 3'-UTR. The average circulating VEGF-A level in Sherpas did not respond to hypoxia at the high altitude in 3440 m, remaining equivalent to the level in non-Sherpa lowlanders at low altitude. Allele discriminations for the analyzed SNPs revealed significant genetic divergences of rs699947, rs8333061, and rs2010963 in Sherpa highlanders compared with non-Sherpa lowlanders, East Asians, South Asians, and the global population; however, consistency with the indigenous Tibetan highlanders from the Tibet Plateau. On the other hand, the SNP rs3025039 in the 3'-UTR presented constant preserved genetic variation among global populations. Our findings indicated that the physiological sea-level VEGF-A concentration in Sherpa highlanders at high altitude was probably linked with the significant variations of VEGFA in Sherpas that regulate the gene expression in a manner of tolerance to hypoxia through production of the optimal biological level of VEGF-A at high altitudes. Precise angiogenesis at high altitude contributes to the adaptive levels of capillary density and microcirculation, providing efficient and effective diffusion of oxygen to tissues and representing human adaptation to high-altitude hypoxia environment. Author summarySherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, partly by one of the adaptation mechanisms promoting increases of microcirculatory blood flow and capillary density at high altitude for restoring oxygen supply to tissues. Vascular endothelial growth factor (VEGF) is mainly stimulated by hypoxia, and is an important signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Interestingly, we found that the circulating VEGF-A level in Sherpa highlanders did not respond to hypoxia at high altitude. Furthermore, allele discrimination of the single nucleotide polymorphisms (SNPs) of VEGFA revealed significant divergences of rs699947, rs8333061, and rs2010963 within the VEGFA regulation region in Sherpa highlanders compared to the non-Sherpa lowlanders, East Asians, South Asians, and the global population; however, consistency with Tibetan highlanders from the Tibet Plateau. We propose that the hypoxia-tolerant circulating VEGF-A level in Sherpa highlanders is linked with the genetic variations of VEGFA, contributing to human adaptation to high-altitude hypoxic environments.

genetics↗