Biology subjects

Takeuchi, F.

Publications and source records attributed to Takeuchi, F..

6 recordsLinked to original sources

bioRxiv2023

Ploidy inference from single-cell data: application to human and mouse cell atlases

Ploidy is relevant to numerous biological phenomena, including development, metabolism, and tissue regeneration. Single-cell RNA-seq and other omics studies are revolutionizing our understanding of biology, yet they have largely overlooked ploidy. This is likely due to the additional assay step required for ploidy measurement. Here, we developed a statistical method to infer ploidy from single-cell ATAC-seq data. When applied to the data from human and mouse cell atlases, our method enabled systematic detection of polyploidy across a range of cell types. This method allows for the integration of ploidy analysis into single-cell studies. Article summaryPloidy plays a crucial role in many biological processes. Though modern studies offer deep insights into biology, they often neglect ploidy because its challenging to measure. In this research, we have created a new method to detect ploidy using single-cell data. This technique helps identify polyploid cells across various cell types, bridging a gap in our understanding.

bioinformatics↗

bioRxiv2023

Granulomatous inflammatory responses are elicited in the liver of PD-1 knockout mice by de novo genome mutagenesis

Aimsprogrammed death-1 (PD-1) is a negative regulator of immune responses. Upon deletion of PD-1 in mice, symptoms of autoimmunity developed only after they got old. In a model experiment in cancer immunotherapy, PD-1 was shown to prevent cytotoxic T lymphocytes from attacking cancer cells that expressed neoantigens derived from genome mutations. Furthermore, the larger number of genome mutations in cancer cells led to the more robust anti-tumor immune responses after the PD-1 blockade. In order to understand the common molecular mechanisms underlying these findings, we hypothesize that we might have acquired PD-1 during evolution in order to avoid/suppress autoimmune reactions against neoantigens derived from mutations in the genome of aged individuals. Main methods: to test the hypothesis, we introduced random mutations into the genome of young PD-1-/- and PD-1+/+ mice. We employed two different procedures of random mutagenesis: administration of a potent chemical mutagen N-ethyl-N-nitrosourea (ENU) into the peritoneal cavity of mice and deletion of MSH2, which is essential for the mismatch-repair activity in the nucleus and, therefore, for the suppression of accumulation of random mutations in the genome. Key findingswe observed granulomatous inflammatory changes in the liver of the ENU-treated PD-1 knockout (KO) mice, but not in the wild-type (WT) counterparts. Such lesions also developed in the PD-1/MSH2 double KO mice, but not in the MSH2 single KO mice. Significance: the results we obtained support our hypothesis: PD-1 probably functions to avoid/suppress inflammatory responses against neoantigens derived from genome mutations in aged individuals.

immunology↗

bioRxiv2023

Genetic reprogramming by brief inhibition of the renin-angiotensin system in spontaneously hypertensive rats leads to persistently reduced kidney renin and low blood pressure.

BACKGROUNDPrevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this reprogramming, but relevant genetic changes are unknown. METHODSIn SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme (ACE) inhibitor, perindopril (with controls for non-specific effects of lowering BP) on differential RNA expression, DNA methylation and renin immunolabelling in the kidney at 20 weeks of age. RESULTSRNA sequencing revealed a 6-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). At 20 weeks, six weeks after treatment cessation, mean arterial pressure remained lower in the treated SHR (P = 0.006), kidney Ren expression was reduced by 23% (P = 0.03) and DNA methylation within the Ren promoter region was increased (P = 0.04). Experiments with the ACE inhibitor perindopril confirmed a long-term reduction in kidney Ren expression of 43% (P = 1.4 x 10-6). Renin immunolabelling was also lower after losartan or perindopril treatment (P = 0.002). RNA sequencing identified differential expression of 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4) and the miRNA miR-145-3p. We found correlations between expression of mRNAs, miRNAs and lncRNAs that we believe represent genetic networks underpinning the decreased Ren expression and lower BP. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS and the kidneys. CONCLUSIONSEarly RAS inhibition in SHR reprograms genetic pathways and networks resulting in a legacy of reduced Ren expression and the persistent reduction in BP.

genetics↗

bioRxiv2022

Single-nucleus ATAC-seq elucidates major modules of gene regulation in the development of non-alcoholic fatty liver disease

We investigated the progression of non-alcoholic fatty liver disease (NAFLD) from fatty liver to steatohepatitis using single-nucleus and bulk ATAC-seq on the livers of rats fed a high-fat diet (HFD). Rats fed HFD for 4 weeks developed fatty liver, and those fed HFD for 8 weeks further progressed to steatohepatitis. We observed an increase in the proportion of inflammatory macrophages, consistent with the pathological progression. Utilizing machine learning, we divided global gene regulation into modules, wherein transcription factors within a module could regulate genes within the same module, reaffirming known regulatory relationships between transcription factors and biological processes. We identified core genes--central to co-expression and protein-protein interaction--for the biological processes discovered. Notably, a large part of the core genes overlapped with genes previously implicated in NAFLD. Single-nucleus ATAC-seq, combined with data-driven statistical analysis, offers insight into in vivo global gene regulation as a combination of modules and assists in identifying core genes of relevant biological processes. Summary blurbThis study uncovers cell type-specific global gene regulation in NAFLD progression, identifying core genes and shedding light on the diseases molecular mechanisms.

genomics↗

bioRxiv2020

Nonlinear ridge regression improves robustness of cell-type-specific differential expression studies

BackgroundEpigenome-wide association studies (EWAS) and differential gene expression analyses are generally performed on tissue samples, which consist of multiple cell types. Cell-type-specific effects of a trait, such as disease, on the omics expression are of interest but difficult or costly to measure experimentally. By measuring omics data for the bulk tissue, cell type composition of a sample can be inferred statistically. Subsequently, cell-type-specific effects are estimated by linear regression that includes terms representing the interaction between the cell type proportions and the trait. This approach involves two issues, scaling and multicollinearity. ResultsFirst, although cell composition is analyzed in linear scale, differential methylation/expression is analyzed suitably in the logit/log scale. To simultaneously analyze two scales, we applied nonlinear regression. Second, we show that the interaction terms are highly collinear, which is obstructive to ordinary regression. To cope with the multicollinearity, we applied ridge regularization. In simulated data, nonlinear ridge regression attained well-balanced sensitivity, specificity and precision. Marginal model attained the lowest precision and highest sensitivity and was the only algorithm to detect weak signal in real data. ConclusionNonlinear ridge regression performed cell-type-specific association test on bulk omics data with well-balanced performance. The omicwas package for R implements nonlinear ridge regression for cell-type-specific EWAS, differential gene expression and QTL analyses. The software is freely available from https://github.com/fumi-github/omicwas

bioinformatics↗

bioRxiv2019

Identification of type 2 diabetes loci in 433,540 East Asian individuals

Meta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.\n\nType 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic {beta} cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

genetics↗