Biology subjects

Fuse, N.

Publications and source records attributed to Fuse, N..

7 recordsLinked to original sources

bioRxiv2026

Folate-dependent one-carbon metabolism controls meiotic and post-meiotic epigenome remodeling in the male germline

Environmental exposures can influence offspring health through epigenetic alterations in the male germline. Folate deficiency, a dietary perturbation that disrupts one-carbon metabolism and S-adenosylmethionine (SAM) production, has been linked to altered histone methylation and developmental abnormalities in offspring. However, when and how folate availability shapes the germline epigenome during spermatogenesis remains unclear. In this study, unbiased metabolomic profiling of spermatogenic cells uncovers stage-specific metabolic remodeling, including downregulation of serine- glycine-one-carbon (SGOC) metabolism in meiotic spermatocytes. Using a post-weaning folate-deficient mouse model, we investigate how folate availability influences germline epigenome establishment during spermatogenesis. Consistent with this metabolic transition, genome-wide chromatin accessibility profiling demonstrates extensive, stage-dependent remodeling under folate-deficient conditions, particularly in meiotic spermatocytes and post-meiotic spermatids. These accessibility changes display cell-type-specific genomic distributions and preferential localization to repressive chromatin compartments in post-meiotic cells. Histone modification analyses further reveal bidirectional redistribution of the active histone mark H3K4me3 in round spermatids. Although genome-wide distribution of the repressive mark H3K27me3 remains largely stable, folate deficiency alters its nuclear organization. Notably, a subset of H3K4me3 alterations established in post-meiotic cells is retained in mature sperm, providing a mechanistic link between paternal metabolic perturbation and the germline epigenome. Together, these findings demonstrate that folate availability shapes germline epigenome establishment through stage-specific metabolic and chromatin remodeling during spermatogenesis, revealing a metabolic basis for paternal environmental effects on the germline epigenome.

developmental biology↗

bioRxiv2024

Blue light toxicity drives the gut microbiota-mediated lipid accumulation in Drosophila

Human agriculture has always raced against insect adaptation, requiring updated pest control methods and knowledge of evolutionary processes. Excessive exposure to blue light (BL) kills a wide range of insect species and has attracted attention as an alternative to chemical pesticides. Here, to understand how insects adapt to BL toxicity, we investigated evolutionary responses to BL toxicity in Drosophila melanogaster over 70 generations using laboratory selection experiments. The selected line exhibited an obese phenotype accompanied by midgut elongation, with BL tolerance dependent on gut microbiota- mediated lipid accumulation. Whole-genome and transcriptome analyses consistently highlighted interactions between the microbiota and host lipid metabolism-related genes. Remarkably, manipulating genes associated with lipid accumulation conferred BL tolerance even in the absence of selection. We suggest that the acquisition of BL tolerance occurs through adaptive obesity. Our study introduces a mechanism of evolutionary adaptation of insects against BL-based selective pressure by maximising the benefits from the gut microbiota via midgut elongation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/608892v5_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@111c9d5org.highwire.dtl.DTLVardef@d9bf7forg.highwire.dtl.DTLVardef@1ab46fborg.highwire.dtl.DTLVardef@1c111cd_HPS_FORMAT_FIGEXP M_FIG C_FIG Brief summaryLaboratory selection for tolerance to blue light toxicity in Drosophila revealed that gut microbiota-mediated obesity, marked by midgut elongation and increased beneficial bacteria, is a key evolutionary adaptation.

evolutionary biology↗

bioRxiv2021

Transcriptome features of trained immunity in Drosophila

Immune memory is an ability of organisms to potentiate immune responses at secondary infection. Current studies have revealed that innate immunity, as well as adaptive immunity, exhibits the memory character called "trained immunity". Although it is suggested that epigenetic reprogramming plays important roles in trained immunity, its underlying mechanism is not fully understood, especially on the individual level. Here we established experimental systems for detecting trained immunity in Drosophila melanogaster. Namely, training infection with low-pathogenic bacteria enhanced the survival rate of the flies at subsequent challenge infection with high-pathogenic bacteria. We found that among low-pathogenic bacteria, Micrococcus luteus (Ml) and Salmonella typhimurium (St) mediated apparent training effects in fly, but seemed to act through different ways. Ml left training effects even after its removal from flies, while living St persisted inside flies for a long time. Our RNA-Seq analysis revealed that Ml-training enhanced the expression of immune-related genes during the challenge infection, but did not do so without challenge infection. In contrast, St-training maintained high expression of the immune-related genes with or without challenge. These results suggest that training effects with Ml and St were due to memory and persistence of immune responses, respectively. Furthermore, we searched the factor involved in Ml-training and identified a candidate, Ada2b, which is a component of the histone modification complex. We found that the Ada2b RNAi and mutant flies showed dampened enhancement of survival rates after Ml-training. These results suggest that Ada2b is involved in the Drosophila trained immunity.

immunology↗

bioRxiv2020

Japonica Array NEO with increased genome-wide coverage and abundant disease risk SNPs

BackgroundIncreasing the power of genome-wide association studies in diverse populations is important for understanding the genetic determinants of disease risks, and large-scale genotype data are collected by genome cohort and biobank projects all over the world. In particular, ethnic-specific SNP arrays are becoming more important because the use of universal SNP arrays has some limitations in terms of cost-effectiveness and throughput. As part of the Tohoku Medical Megabank Project, which integrates prospective genome cohorts into a biobank, we have been developing a series of Japonica Arrays for genotyping participants based on reference panels constructed from whole-genome sequence data of the Japanese population. ResultsWe designed a novel version of the SNP Array for the Japanese population, called Japonica Array NEO, comprising a total of 666,883 SNPs, including tag SNPs of autosomes and X chromosome with pseudoautosomal regions, SNPs of Y chromosome and mitochondria, and known disease risk SNPs. Among them, 654,246 tag SNPs were selected from an expanded reference panel of 3,552 Japanese using pairwise r2 of linkage disequilibrium measures. Moreover, 28,298 SNPs were included for the evaluation of previously identified disease risk SNPs from the literature and databases, and those present in the Japanese population were extracted using the reference panel. The imputation performance of Japonica Array NEO was assessed by genotyping 286 Japanese samples. We found that the imputation quality r2 and INFO score in the minor allele frequency bin >2.5%-5% were >0.9 and >0.8, respectively, and >12 million markers were imputed with an INFO score >0.8. After verification, Japonica Arrays were used to efficiently genotype cohort participants from the sample selection to perform a quality assessment of the raw data; approximately 130,000 genotyping data of >150,000 participants has already been obtained. ConclusionsJaponica Array NEO is a promising tool for genotyping the Japanese population with genome-wide coverage, contributing to the development of genetic risk scores for this population and further identifying disease risk alleles among individuals of East Asian ancestry.

genomics↗

bioRxiv2020

Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes in a 3,552 Japanese whole-genome sequence dataset (3.5KJPNv2)

Identification of pathogenic germline variants yet no clinical evidence in BRCA genes has become important in patient care of hereditary breast and ovarian cancer syndrome (HBOC). Computational scoring and prospective cohort studies may help to identify such pathogenic variants. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of the genome cohorts by Tohoku Medical Megabank Project (TMM) with the InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAF) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar are used for filtration criteria. Familial predispositions in cancers among the 35,000 TMM genome cohort participants are analyzed to verify the pathogenicity. Seven potentially pathogenic variants were newly identified. Carriers of these potential pathogenic variants and definite P and LP variants among participants of the TMM prospective cohort show a statistically significant preponderance in cancer onset in sisters in the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potential pathogenic variants in BRCA genes for Japanese population. These results will be helpful to follow up the carriers of variants of uncertain significance in the HBOC genes.

genetics↗

bioRxiv2019

3.5KJPNv2, An allele frequency panel of 3,552 Japanese Individuals

The first step towards realizing personalized healthcare is to catalog the genetic variations in a population. Since the dissemination of individual-level genomic information is strictly controlled, it will be useful to construct population-level allele frequency panels and to provide them through easy-to-use interfaces. In the Tohoku Medical Megabank Project, we have sequenced nearly 4,000 individuals from a Japanese population, and constructed an allele frequency panel of 3,552 individuals after removing related samples. The panel is called the 3.5KJPNv2. It was constructed by using a standard pipeline including the 1KGP and gnomAD algorithms to reduce technical biases and to allow comparisons to other populations. Our database is the first largescale panel providing the frequencies of variants present on the X chromosome and on the mitochondria in the Japanese population. All the data are available on our original database at https://jmorp.megabank.tohoku.ac.jp.

genomics↗

bioRxiv2018

Frequent variants in the Japanese population determine quasi-Mendelian inheritance of rare retinal ciliopathy

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e. a 3.5-fold enrichment; p-value = 9.2x10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation, in trans with the Alu insertion, but might also cause disease in association with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

genomics↗