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Biology subjects

Sekiya, M.

Publications and source records attributed to Sekiya, M..

7 recordsLinked to original sources

Multimodal phenotyping reveals plant-food-related dietary information in serum Raman spectra of community-dwelling Japanese adults

Healthy dietary patterns are associated with long-term health, but diet-quality scores do not reveal how habitual dietary information is represented in human biological phenotypes. Here we linked habitual dietary assessment with preceding health records and contemporaneous clinical chemistry, serum metabolomics and serum Raman spectra in community-dwelling Japanese adults. Higher diet quality corresponded to a more favorable preceding health profile, but did not define discrete states across contemporary multivariate phenotypes. Instead, specific dietary information was recoverable across these layers: Raman spectra provided predictive information complementary to clinical and metabolomic measurements for multiple dietary variables. Raman variation corresponding to {beta}-carotene equivalent could be traced to carotenoid-assigned bands and aligned with a broader plant-food-related dietary dimension. These findings show that habitual diet is represented not as a single biological state but through biologically traceable dietary dimensions distributed across complementary phenotypic layers.

bioinformatics↗

CH-related Mutant ASXL1 Promotes Atherosclerosis in Mice via Dysregulated Innate Immunity

Certain somatic mutations confer a fitness advantage in hematopoietic stem and progenitor cells (HSPCs) over normal HSPCs, resulting in the clonal expansion of mutant blood cells1, otherwise known as clonal haematopoiesis (CH). CH is frequently observed among healthy elderly people and is closely associated with the risk of cardiovascular diseases (CVDs). The most frequently mutated genes of CH include DNMT3A, TET2, and ASXL12. Among them, even though ASXL1 mutations are clinically associated with the highest risk for developing CVDs, little is known whether and how the mutations contribute to CVDs. Here we show accelerated development of atherosclerosis and increased inflammatory monocytes in mice transplanted with the bone marrow cells (BMCs) from the mice expressing mutant ASXL1 (ASXL1-MT) selectively in hematopoietic cells. RNA sequencing analysis of the plaque-macrophages derived from BMCs expressing ASXL1-MT showed more inflammatory signatures than those from control BMCs. Mechanistically, wild-type ASXL1 inhibited innate immune signalling through direct interactions with IRAK1/TRAF6/TAK1 in the cytoplasm, while ASXL1-MT, which only interacted with TAK1, lost this regulatory function, leading to NF-{kappa}B activation. This mechanism is unique and distinct from those of CH with Tet2 or Dnmt3a mutations, where overactivation of the IL-1{beta}/NLRP3 inflammasome plays critical roles3-5. Intriguingly, IRAK1/4 inhibition decreased the number of inflammatory monocytes and attenuated the development of atherosclerosis driven by ASXL1-MT. The present work connects the mutations of an epigenetic factor, ASXL1, with inflammation and CVDs and gives an indication for the prevention of CVDs in CH.

cell biology↗

Label-free imaging of cellular organization in living mammalian cells via external apodization phase-contrast microscopy

Developing techniques to visualize intracellular structures, which influence the spatiotemporal functionality of biomolecules, is essential for elucidating mechanisms governing cellular behavior. In this study, we demonstrate that label-free external apodization phase-contrast (ExAPC) microscopy serves as a valuable tool for the simultaneous observation of various intracellular structures with high spatiotemporal resolution, while successfully mitigating halo artifacts. Additionally, through quantitative analysis of images obtained by combining ExAPC microscopy with fluorescence microscopy, we identified distinct heterogeneities in biomolecular condensates, lipid droplets, and mitochondria. Our findings highlight the potential of ExAPC microscopy to provide detailed insights into alterations in intracellular structures associated with diverse cellular processes, corroborating the existing knowledge and potentially contributing to the discovery of novel cellular mechanisms.

cell biology↗

Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at ER monitoring and regulating fatty acids

The ER-embedded transcription factors, sterol-regulatory element-binding proteins (SREBPs), master regulators of lipid biosynthesis, are transported to Golgi for proteolytic activation to tune cellular cholesterol levels and regulate lipogenesis. However, mechanisms by which the cell responds to the levels of saturated or unsaturated fatty acids remain underexplored. Here we show that RHBDL4/RHBDD1, a rhomboid family protease, directly cleaves SREBP-1c at ER. The p97/VCP, AAA-ATPase complex then acts as an auxiliary segregase to extract the remaining ER-embedded fragment of SREBP-1c. Importantly, the enzymatic activity of RHBDL4 is enhanced by saturated fatty acids (SFAs), but inhibited by polyunsaturated fatty acids (PUFAs). Genetic deletion of RHBDL4 in mice fed on a Western diet enriched in SFAs and cholesterol prevented SREBP-1c from inducing genes for lipogenesis, particularly for synthesis and incorporation of PUFAs, and secretion of lipoproteins. The RHBDL4-SREBP-1c pathway reveals a regulatory system for monitoring fatty acid composition and maintaining cellular lipid homeostasis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/457590v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@591eb2org.highwire.dtl.DTLVardef@ee6361org.highwire.dtl.DTLVardef@be893eorg.highwire.dtl.DTLVardef@1247d38_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

Disentangling the biological information encoded in disordered mitochondrial morphology through its rapid elicitation by iCMM

Mitochondrial morphology is dynamically changed in conjunction with spatiotemporal functionality. Although considerable efforts have been made to understand why abnormal mitochondrial morphology occurs in various diseases, the biological significance of mitochondrial morphology in states of health and disease remains to be elucidated owing to technical limitations. In the present study, we developed a novel method, termed inducible Counter Mitochondrial Morphology (iCMM), to purposely manipulate mitochondrial morphological patterns on a minutes timescale, using a chemically inducible dimerization system. Using iCMM, we showed that mitochondrial morphological changes rapidly lead to the characteristic reconstitution of various biological information, which is difficult to investigate by conventional genetic engineering. The manipulation of mitochondrial morphology using iCMM can improve our understanding of the interplay between mitochondrial morphology and cellular functions.Competing Interest StatementThe authors have declared no competing interest.View Full Text

synthetic biology↗

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

To study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimers Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H+-ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.

neuroscience↗

Disruption of a RAC1-centred protein interaction network is associated with Alzheimer’s disease pathology and causes age-dependent neurodegeneration

The molecular biological mechanisms of Alzheimers disease (AD) involve disease-associated cross-talk through many genes and include a loss of normal as well as a gain of abnormal interactions among genes. A protein domain network (PDN) is a collection of physical bindings that occur between protein domains, and the states of the PDNs in patients with AD are likely to be perturbed compared to those in normal healthy individuals. To identify PDN changes that cause neurodegeneration, we analysed the PDNs that occur among genes co-expressed in each of three brain regions at each stage of AD. Our analysis revealed that the PDNs collapsed with the progression of AD stage and identified five hub genes, including Rac1, as key players in PDN collapse. Using publicly available gene expression data, we confirmed that the mRNA expression level of the RAC1 gene was downregulated in the entorhinal cortex (EC) of AD brains. To test the causality of these changes in neurodegeneration, we utilized Drosophila as a genetic model and found that modest knockdown of Rac1 in neurons was sufficient to cause age-dependent behavioural deficits and neurodegeneration. Finally, we identified a microRNA, hsa-miR-101-3p, as a potential regulator of RAC1 in AD brains. As the Braak neurofibrillary tangle (NFT) stage progressed, the expression levels of hsa-miR-101-3p were upregulated specifically in the EC. Furthermore, overexpression of hsa-miR-101-3p in the human neuronal cell line SH-SY5Y caused RAC1 downregulation. These results highlight the utility of our integrated network approach for identifying causal changes leading to neurodegeneration in AD.

genomics↗