Biology subjects

Nishio, H.

Publications and source records attributed to Nishio, H..

8 recordsLinked to original sources

bioRxiv2025

Conserved gene- and network-level thermal memory intervals in two divergent perennial crucifers in nature

Some biological responses persist long after the initial stimulus has disappeared--a phenomenon known as cellular memory. In its long-term form, cellular memory often reflects interactions between cis-acting chromatin states and diffusible trans-acting regulators, which are experimentally difficult to separate in vivo. A key challenge is to develop a quantitative framework that captures cellular memory length even without prior mechanistic knowledge. The FLOWERING LOCUS C (FLC) gene illustrates this problem and opportunity: a Polycomb/Trithorax cis-acting chromatin switch at FLC produces bistable ON/OFF transcriptional states, while trans-acting factors such as VIN3 and FT modulate transitions between those states. In laboratory studies, FLC memory is classically viewed as persistence of repression or activation after the inducing signal disappears; field studies additionally show that FLC integrates fluctuating temperatures over past intervals, revealing time-integrative mode of memory. To quantify such long-term effects systematically, we formalized the thermal memory interval (TMI), the time window of past environmental cues that best predicts current gene expression--as a transferable metric. We applied TMI to the VIN3-FLC-FT module in two perennial Brassicaceae with divergent life histories: Arabidopsis halleri subsp. gemmifera, an established ecological model, and Eutrema japonicum, introduced here to identify features generalizable beyond a single species. Using long-term expression and meteorological data, TMIs distinguished spring versus autumn FLC states and revealed distributed memory across the VIN3-FLC-FT network, with intervals from 1-150 days, extending previously reported FLC timescales. While TMIs require dense time-series data and do not by themselves reveal molecular mechanism, they offer a robust, quantitative, and generalizable framework: TMIs can be extended to other genes and to alternative environmental or physiological variables, enabling direct, comparative quantification of cellular memory across genes, species, and contexts.

molecular biology↗

bioRxiv2025

H3K4me2 orchestrates H2A.Z and Polycomb repressive marks in Arabidopsis

The dimethylation of histone H3 lysine 4 (H3K4me2) plays an important role in developmental phase transitions in plants, such as regeneration from the callus and the initiation of flowering. H3K4me2 in plants is correlated with transcriptionally repressed states, which can be accounted for by transcription-coupled active H3K4me2 demethylation, but the converse molecular pathway by which H3K4me2 represses transcription remains largely unexplored. Here, we show that H3K4me2 colocalizes with the facultatively repressive marks H2A.Z, H2A ubiquitination (H2Aub), and H3K27me3 in the gene body. Our genetic analyses reveal that H3K4me2 functions upstream but not downstream of these repressive marks. Interestingly, in genes with diurnal H3K4me2 oscillation, H3K4me2 oscillates in antiphase with transcription but in phase with H2A.Z. In addition, the genetic manipulation of H3K4me2 affects the oscillating profiles of H2A.Z, suggesting the efficient relay from H3K4me2 to H2A.Z. Notably, the diurnal oscillation of H2Aub is much weaker than that of H2A.Z despite the overall similarity in their distributions. These results suggest that H3K4me2 orchestrates H2A.Z and H2Aub with distinct dynamics. Our findings reveal that plants employ H3K4me2 to transmit transcriptional cessation into repressive chromatin states.

genetics↗

bioRxiv2024

A novel RyR2-selective stabilizer prevents and ameliorates severe arrhythmias in stress-induced ventricular tachycardia

Background and PurposeAberrant activation of the type 2 ryanodine receptor (RyR2) causes lethal arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Developing drugs that suppress RyR2 hyperactivation may be key to novel arrhythmia treatments. This study evaluated the antiarrhythmic potential of Ryanozole, a recently developed novel RyR2 modulator with high affinity and selectivity, using CPVT mouse models harboring mutant RyR2s. Experimental approachIn vitro effects of Ryanozole were evaluated by ER Ca2+-based assay and [3H]Ryanodine binding assay using RyR2-expressing HEK293 cells. Two lines of mice with different arrhythmia severity, RyR2-R420W and -K4750Q, were employed for in vivo assessments. Intracellular Ca2+ signals were analyzed in isolated cardiomyocytes using Cal520. Antiarrhythmic effects were evaluated by ECG under catecholaminergic challenge in anesthetized mice and during spontaneous arrhythmias in conscious mice. ECG and echocardiographic parameters were evaluated before and after drug administration. Key resultsRyanozole inhibited both wild type and mutant RyR2s with similar IC50 of 15-40 nM. The inhibition was more potent at lower cytosolic Ca2+ concentrations. It suppressed Ca2+ waves and Ca2+ sparks without affecting action potential-evoked Ca2+ transients. Ryanozole effectively prevented adrenaline-induced arrhythmias and rapidly terminated spontaneous arrhythmias during daily activity. Importantly, Ryanozole did not impair cardiac conduction or contractility, unlike conventional antiarrhythmic drugs. Conclusions and implicationsRyanozole strongly suppresses RyR2 under diastolic Ca2+ conditions, thereby preventing the arrhythmogenic trigger of aberrant Ca2+ release. This mechanism likely provides potent antiarrhythmic effects while preserving cardiac function. Ryanozole is a promising therapeutic candidate treating RyR2-mediated arrhythmias, such as CPVT.

pharmacology and toxicology↗

bioRxiv2024

Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity

The adaptive T cell response is accompanied by continuous rewiring of the T cells electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.

immunology↗

bioRxiv2023

Anodal M1 tDCS enhances online learning of rhythmic timing videogame skill

Transcranial direct current stimulation (tDCS) has been shown to modify excitability of the primary motor cortex (M1) and influence online motor learning. However, research on the effects of tDCS on motor learning has focused predominantly on simplified motor tasks. The purpose of the present study was to investigate whether anodal stimulation of M1 over a single session of practice influences online learning of a relatively complex rhythmic timing video game. Fifty-eight healthy young adults were randomized to either a-tDCS or SHAM conditions and performed 2 familiarization blocks, a 20-minute 5 block practice period while receiving their assigned stimulation, and a post-test block with their non-dominant hand. To assess performance, a performance index was calculated that incorporated timing accuracy elements and incorrect key inputs. The results showed that M1 a-tDCS enhanced the learning of the video game based skill more than SHAM stimulation during practice, as well as overall learning at the post-test. These results provide evidence that M1 a-tDCS can enhance acquisition of skills where quality or success of performance depends on optimized timing between component motions of the skill, which could have implications for the application of tDCS in many real-world contexts.

neuroscience↗

bioRxiv2023

Screening for novel RyR2 inhibitors by ER Ca2+ monitoring

Type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic/sarcoplasmic reticulum (ER/SR) that plays a central role in the excitation-contraction coupling in the heart. Hyperactivity of RyR2 has been linked to ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) and heart failure, where spontaneous Ca2+ release via hyperactivated RyR2 depolarizes diastolic membrane potential to induce triggered activity. In such cases, drugs that suppress RyR2 activity are expected to prevent the arrhythmias, but there is no clinically available RyR2 inhibitors at present. In this study, we searched for RyR2 inhibitors from a well-characterized compound library using a recently developed ER Ca2+-based assay, where the inhibition of RyR2 activity was detected by the increase in ER Ca2+ signals from R-CEPIA1er, a genetically encoded ER Ca2+ indicator, in RyR2-expressing HEK293 cells. By screening 1535 compounds in the library, we identified three compounds (chloroxylenol, methyl orsellinate and riluzole) that greatly increased the ER Ca2+ signal. All of the three compounds suppressed spontaneous Ca2+ oscillations in RyR2-expressing HEK293 cells and correspondingly reduced the Ca2+-dependent [3H]ryanodine binding activity. In cardiomyocytes from RyR2-mutant mice, the three compounds effectively suppressed abnormal Ca2+ waves without substantial effects on the action-potential-induced Ca2+ transients. These results confirm that ER Ca2+-based screening is useful for identifying modulators of ER Ca2+ release channels and suggest that RyR2 inhibitors have potential to be developed as a new category of antiarrhythmic drugs. Significance statementWe successfully identified three compounds having RyR2 inhibitory action from a well-characterized compound library using an ER Ca2+-based assay, and demonstrated that these compounds suppressed arrhythmogenic Ca2+ wave generation without substantially affecting physiological action-potential induced Ca2+ transients in cardiomyocytes. This study will facilitate the development of RyR2 specific inhibitors as a potential new class of drugs for life-threatening arrhythmias induced by hyperactivation of RyR2.

pharmacology and toxicology↗

bioRxiv2022

Circadian and environmental signal transduction in a natural population of Arabidopsis

Plants sense and respond to environmental cues during 24 h fluctuations in their environment. This requires the integration of internal cues such as circadian timing with environmental cues such as light and temperature to elicit cellular responses through signal transduction. However, the integration and transduction of circadian and environmental signals within plants growing in natural environments remains poorly understood. To gain insights into the 24 h dynamics of environmental signalling in nature, we performed a field study of signalling from the nucleus to chloroplasts in a natural population of Arabidopsis halleri. Using advanced modelling approaches to interpret the data, we identified that the circadian clock and temperature are key regulators of this pathway under natural conditions. We identified potential time-delay steps between pathway components, and diel fluctuations in the response of the pathway to temperature cues that are reminiscent of the process of circadian gating. This approach of combining studies of gene expression in the field with modelling allowed us to identify the dynamic integration and transduction of environmental cues, in plant cells, under naturally fluctuating diel cycles.

plant biology↗

bioRxiv2019

Seasonal stability and dynamics of DNA methylation in plants in a natural environment

Organisms survive in naturally fluctuating environments by responding to long-term signals, such as seasonality, by filtering out short-term noise. DNA methylation has been considered a stable epigenetic mark but has also been reported to change in response to experimental manipulations of biotic and abiotic factors. However, it is unclear how they behave in natural environments. Here, we analyzed seasonal patterns of genome-wide DNA methylation at a single-base resolution using a single clone from a natural population of the perennial Arabidopsis halleri. The genome-wide pattern of DNA methylation was primarily stable, and most of the repetitive regions were methylated across the year. Although the proportion was small, we detected seasonally methylated cytosines (SeMCs) in the genome. SeMCs in the different contexts showed distinct seasonal patterns of methylation. SeMCs in CHH context were detected predominantly at repetitive sequences in intergenic regions. Additionally, we found that CHH methylation within AhgFLC locus showed a seasonal pattern that was negatively associated with changes in gene expression. Gene-body CG methylation (gbM) itself was generally stable across seasons, but the levels of gbM were positively associated with seasonal stability of RNA expression of the genes. These results suggest the existence of two distinct aspects of DNA methylation in natural environments: sources of epigenetic variation and epigenetic marks for stable gene expression.

plant biology↗