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Exploring the genomic and transcriptomic profiles of glycemic traits and drug repurposing

Journal of Biomedical Science 2025年第1期32卷 1-14页

作者： Lin, Min-Rou Tsai, Cheng-Lin Liao, Cai-Sian Wei, Chun-Yu Chou, Wan-Hsuan Hsiao, Tzu-Hung Chang, Wei-Chiao Department of Clinical Pharmacy School of Pharmacy Taipei Medical University Taipei Taiwan Bioinformatics Program Institute of Statistical Science Taiwan International Graduate Program Academia Sinica Taipei Taiwan Bioinformatics Program Taiwan International Graduate Program National Taiwan University Taipei Taiwan Core Laboratory of Neoantigen Analysis for Personalized Cancer Vaccine Office of R&D Taipei Medical University Taipei Taiwan Department of Medical Research Taichung Veterans General Hospital Taichung Taiwan Department of Public Health Fu Jen Catholic University New Taipei City Taiwan Institute of Genomics and Bioinformatics National Chung Hsing University Taichung Taiwan Master Program in Clinical Genomics and Proteomics School of Pharmacy Taipei Medical University Taipei Taiwan Integrative Research Center in Critical Care Wan Fang Hospital Taipei Medical University Taipei Taiwan

Type 2 diabetes is an increasingly prevalent metabolic disorder with moderate to high heritability. Glycemic indices are crucial for diagnosing and monitoring the disease. Previous genome-wide association study (GWAS) have identified several risk loci associated with type 2 diabetes, but data from the Taiwanese population remain relatively sparse and primarily focus on type 2 diabetes status rather than glycemic trait levels. We conducted a comprehensive genome-wide meta-analysis to explore the genetics of glycemic traits. The study incorporated a community-based cohort of 145,468 individuals and a hospital-based cohort of 35,395 individuals. The study integrated genetics, transcriptomics, biological pathway analyses, polygenic risk score calculation, and drug repurposing for type 2 diabetes. This study assessed hemoglobin A1c and fasting glucose levels, validating known loci (FN3K, SPC25, MTNR1B, and FOXA2) and discovering new genes, including MAEA and PRC1. Additionally, we found that diabetes, blood lipids, and liver- and kidney-related traits share genetic foundations with glycemic traits. A higher PRS was associated with an increased risk of type 2 diabetes. Finally, eight repurposed drugs were identified with evidence to regulate blood glucose levels, offering new avenues for the management and treatment of type 2 diabetes. This research illuminates the unique genetic landscape of glucose regulation in Taiwanese Han population, providing valuable insights to guide future treatment strategies for type 2 diabetes.

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Genomic data processing with GenomeFlow

arXiv

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arXiv 2025年

作者： Park, Junseok Maury, Eduardo A. Oh, Changhoon Shin, Donghoon Denisko, Danielle Lee, Eunjung Alice Division of Genetics and Genomics Boston Children’s Hospital 3 Blackfan Circle BostonMA United States Department of Pediatrics Harvard Medical School 25 Shattuck St BostonMA United States Bioinformatics Integrative Genomics Program Harvard/MIT MD-PHD Program Harvard Medical School BostonMA United States Program in Medical and Population Genetics Broad Institute of MIT and Harvard CambridgeMA United States Graduate School of Information Yonsei University 50 Yonsei-ro Seodaemun-gu Seoul Korea Republic of Department of Human Centered Design and Engineering University of Washington SeattleWA United States Department of Biomedical Informatics Harvard Medical School BostonMA United States

Advances in genome sequencing technologies generate massive amounts of sequence data that are increasingly analyzed and shared through public repositories. On-demand infrastructure services on cloud computing platforms enable the processing of such large-scale genomic sequence data in distributed processing environments with a significant reduction in analysis time. However, parallel processing on cloud computing platforms presents many challenges to researchers, even skillful bioinformaticians. In particular, it is difficult to design a computing architecture optimized to reduce the cost of computing and disk storage as genomic data analysis pipelines often employ many heterogeneous tools with different resource requirements. To address these issues, we developed GenomeFlow, a tool for automated development of computing architecture and resource optimization on Google Cloud Platform, which allows users to process a large number of samples at minimal cost. We outline multiple use cases of GenomeFlow demonstrating its utility to significantly reduce computing time and cost associated with analyzing genomic and transcriptomic data from hundreds to tens of thousands of samples from several consortia. Here, we describe a step-by-step protocol on how to use GenomeFlow for a common genomic data processing task. We introduce this example protocol geared toward a bioinformatician with little experience in cloud computing. © 2025, CC BY.

关键词： Cloud platforms

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Plant biotic interactions

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Journal of integrative Plant Biology 2016年第4期58卷 282-283页

作者： Hailing Jin Special Issue EditorUC President's Chair Director of Genetics Genomics and Bioinformatics Graduate ProgramCenter for Plant Cell BiologyInstitute for Integrative Genome BiologyUniversity of CaliforniaRiversideUSA

Plants are constantly under attack by pathogens,pests,and parasites,resulting in severe consequences on global food production and human *** pathogens and pests find their ways to invade and communicate with their hos... 详细信息

关键词： communicate constantly sophisticated consequences microbial fight biotic evolved pathogen volatile

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Regulation of the SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE genes/microRNA 156 Module by the Homeodomain Proteins PENNYWISE and POUND-FOOLISH in Arabidopsis

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Molecular Plant 2011年第6期4卷 1123-1132页

作者： Shruti Lal Leo Bryan Pacis Harley M.S. Smith Genetics Genomics and Bioinformatics Graduate Program University of California Riverside CA 92521 USA Center for Plant Cell Biology Institute of Integrative Genome Biology Department of Botany and Plant Sciences University of California Riverside CA 92521 USA

The morphology of inflorescences is regulated in part by the temporal and spatial events that regulate flower specification. In Arabidopsis, an endogenous flowering time pathway mediated by a subset of SQUAMOSA PROMOTER- BINDING PROTEIN-LIKE （SPL） transcription factors, including SPL3, SPL4, and SPL5, function to specify flowers by activating floral meristem identity genes. During shoot development, SPL3, SPL4, and SPL5 are post-transcriptionally regulated by microRNA156 （miR156）. The photoperiod regulated florigenic signal, FLOWERING LOCUS T （FT）, promotes floral induction, in part by activating SPL3, SPL4, and SPL5. In turn, these SPLs function in parallel with FT to specify flower meristems. Two related BELLl-like homeobox genes PENNYWISE （PNY） and POUND-FOOLISH （PNF） expressed in the shoot apical meristem are absolutely required for the specification of floral meristems. Genetic studies show that the floral specification function of FT depends upon PNYand PNF; however, the interplay between these homeodomain proteins and SPLs is not known. In this manuscript, we show that the photoperiodic floral induction of SPL3, SPL4, and SPL5 is dependent upon PNY and PNE Further, PNY and PNF also control SPL3, SPL4, and SPL5 expression by negatively regulating miR156. Lastly, ectopic expres- sion of SPL4 partially rescues the pny pnf non-flower-producing phenotype, while overexpression of SPL3 or SPL5 in pny pnf plants was unable to restore flower specification. These results suggest that：（1） SPL3, SPL4, and SPL5 function is dependent upon PNY and PNF, or （2） expression of multiple SPLs is required for floral specification in pny pnf plants.

关键词： Development meristem homeodomain flowering microRNA.

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Nanoparticles may influence mast cells gene expression profiles without affecting their degranulation function

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Nanomedicine: Nanotechnology, Biology, and Medicine 2025年 66卷 102818-102818页

作者： Newton, Hannah S. Cedrone, Edward Grunberger, Jason Xie, Shaojun Zhao, Yongmei Tran, Bao Toms, Bradley S. Xu, Weining Plant-Hately, Alexander Liptrott, Neill J. Dobrovolskaia, Marina A. Nanotechnology Characterization Lab. Cancer Research Technology Program Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute FrederickMD21702 United States Utah Center for Nanomedicine Department of Molecular Pharmaceutics University of Utah Salt Lake CityUT United States Sequencing Facility Bioinformatics Group Biomedical Informatics and Data Science Directorate Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute FrederickMD21702 United States CCR Sequencing Facility Cancer Research Technology Program Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute FrederickMD21702 United States 10x Genomics Inc. PleasantonCA94588-3260 United States Immunocompatibility Group Department of Pharmacology and Therapeutics Institute of Systems Molecular and Integrative Biology University of Liverpool LiverpoolL7 3NY United Kingdom Institute of Systems Molecular and Integrative Biology University of Liverpool LiverpoolL7 8TX United Kingdom

An in vitro method for monitoring nanoparticle effects on IgE-dependent mast cell degranulation was developed and validated. The assayed nanoparticles included four clinical-grade nanomedicines (Abraxane, Doxil, AmBisome, and Feraheme) and three commercial research-grade nanomaterials (generation 5 PAMAM dendrimers with carboxy-, hydroxy-, or amine- surface functionalities). Most of the tested materials did not alter IgE-dependent mast cell degranulation, suggesting that nanoparticles and nanomedicines are unlikely to worsen pre-existing allergies to other antigens. Two clinical-grade formulations containing cytotoxic oncology drugs—Abraxane and Doxil—decreased degranulation. Abraxane but not Doxil decreased FcΕR expression on the cell surface. Single-cell sequencing revealed the most differentially expressed genes (DEG) in Abraxane and Doxil-treated cultures. Interestingly, Feraheme and amine-terminated dendrimers induced DEG without affecting degranulation. These data demonstrate that some nanomaterials have more effects on immune cells than can be detected by a functional immunoassay. © 2025 Elsevier Inc.

关键词： Nanoclay

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Bile acid synthesis impedes tumor-specific T cell responses during liver cancer

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Science (New York, N.Y.) 2025年第6730期387卷 192-201页

作者： Varanasi, Siva Karthik Chen, Dan Liu, Yingluo Johnson, Melissa A. Miller, Cayla M. Ganguly, Souradipta Lande, Kathryn LaPorta, Michael A. Hoffmann, Filipe Araujo Mann, Thomas H. Teneche, Marcos G. Casillas, Eduardo Mangalhara, Kailash C. Mathew, Varsha Sun, Ming Jensen, Isaac J. Farsakoglu, Yagmur Chen, Timothy Parisi, Bianca Deota, Shaunak Havas, Aaron Lee, Jin Chung, H Kay Schietinger, Andrea Panda, Satchidananda Williams, April E. Farber, Donna L. Dhar, Debanjan Adams, Peter D. Feng, Gen-Sheng Shadel, Gerald S. Sundrud, Mark S. Kaech, Susan M. NOMIS Center for Immunobiology and Microbial Pathogenesis Salk Institute for Biological Studies La Jolla CA United States Department of Pathology School of Medicine University of California San Diego La Jolla CA United States Sanford Burnham Prebys Medical Discovery Institute La Jolla CA United States Department of Medicine School of Medicine University of California San Diego CA United States Razavi Newman Integrative Genomics and Bioinformatics Core Facility Salk Institute for Biological Studies La Jolla CA United States Department of Microbiology and Immunology Columbia University Irving Medical Center New York NY USA Department of Surgery Columbia University Irving Medical Center New York NY USA Regulatory Biology Laboratory Salk Institute for Biological Studies La Jolla CA United States Immunology Program Memorial Sloan Kettering Cancer Center New York NY USA Immunology and Microbial Pathogenesis Program Weill Cornell Graduate School of Medical Sciences New York NY USA Parker Institute for Cancer Immunotherapy New York NY USA Department of Microbiology and Immunology Geisel School of Medicine at Dartmouth Hanover NH USA Department of Medicine Geisel School of Medicine at Dartmouth Hanover NH USA Center for Digestive Health Dartmouth Health NH United States Dartmouth Cancer Center Dartmouth Health NH United States

The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. Furthermore, different BAs regulated CD8+ T cells differently;primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.

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Distinguishing genetic correlation from causation across 52 diseases and complex traits (vol 50, pg 1728, 2018)

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NATURE GENETICS 2018年第12期50卷 1753-1753页

作者： O'Connor, Luke J. Price, Alkes L. Department of Epidemiology Harvard T.H. Chan School of Public Health Boston MA USA Program in Bioinformatics and Integrative Genomics Harvard Graduate School of Arts and Sciences Cambridge MA USA Department of Biostatistics Harvard T.H. Chan School of Public Health Boston MA USA Program in Medical and Population Genetics Broad Institute Cambridge MA USA

Mendelian randomization, a method to infer causal relationships, is confounded by genetic correlations reflecting shared etiology. We developed a model in which a latent causal variable mediates the genetic correlation; trait 1 is partially genetically causal for trait 2 if it is strongly genetically correlated with the latent causal variable, quantified using the genetic causality proportion. We fit this model using mixed fourth moments \({\it{E}}({\it{\alpha }}_1^2{\it{\alpha }}_1{\it{\alpha }}_2)\) and \({\it{E}}\left( {{\it{\alpha }}_2^2{\it{\alpha }}_1{\it{\alpha }}_2} \right)\) of marginal effect sizes for each trait; if trait 1 is causal for trait 2, then SNPs affecting trait 1 (large \({\it{\alpha }}_1^2\)) will have correlated effects on trait 2 (large α₁α₂), but not vice versa. In simulations, our method avoided false positives due to genetic correlations, unlike Mendelian randomization. Across 52 traits (average n = 331,000), we identified 30 causal relationships with high genetic causality proportion estimates. Novel findings included a causal effect of low-density lipoprotein on bone mineral density, consistent with clinical trials of statins in osteoporosis.

关键词： Genetics Genome-wide association studies

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Distinct adipose progenitor cells emerging with age drive active adipogenesis

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Science (New York, N.Y.) 2025年第6745期388卷 eadj0430页

作者： Wang, Guan Li, Gaoyan Song, Anying Zhao, Yutian Yu, Jiayu Wang, Yifan Dai, Wenting Salas, Martha Qin, Hanjun Medrano, Leonard Dow, Joan Li, Aimin Armstrong, Brian Fueger, Patrick T. Yu, Hua Zhu, Yi Shao, Mengle Wu, Xiwei Jiang, Lei Campisi, Judith Yang, Xia Wang, Qiong A. Department of Molecular and Cellular Endocrinology Arthur Riggs Diabetes and Metabolism Research Institute City of Hope Medical Center Duarte CA USA Department of Integrative Biology and Physiology University of California Los Angeles CA United States Light Microscopy Core City of Hope Medical Center Duarte CA USA The Integrative Genomics Core City of Hope Medical Center Duarte CA USA Division of Developmental and Translational Diabetes and Endocrinology Research City of Hope Medical Center Duarte CA USA Comprehensive Metabolic Phenotyping Core City of Hope Medical Center Duarte CA USA Pathology Core of Shared Resources City of Hope Medical Center Duarte CA USA Comprehensive Cancer Center Beckman Research Institute City of Hope Medical Center Duarte CA USA Children's Nutrition Research Center Department of Pediatrics Baylor College of Medicine Houston TX United States Key Laboratory of Immune Response and Immunotherapy Shanghai Institute of Immunity and Infection Chinese Academy of Sciences Shanghai China Buck Institute for Research on Aging Novato CA United States Bioinformatics Interdepartmental Program University of California Los Angeles CA United States Institute for Quantitative and Computational Biosciences University of California Los Angeles CA United States Molecular and Medical Pharmacology University of California Los Angeles CA United States

Starting at middle age, adults often suffer from visceral adiposity and associated adverse metabolic disorders. Lineage tracing in mice revealed that adipose progenitor cells (APCs) in visceral fat undergo extensive adipogenesis during middle age. Thus, despite the low turnover rate of adipocytes in young adults, adipogenesis is unlocked during middle age. Transplantations quantitatively showed that APCs in middle-aged mice exhibited high adipogenic capacity cell-autonomously. Single-cell RNA sequencing identified a distinct APC population, the committed preadipocyte, age-enriched (CP-A), emerging at this age. CP-As demonstrated elevated proliferation and adipogenesis activity. Pharmacological and genetic manipulations indicated that leukemia inhibitory factor receptor signaling was indispensable for CP-A adipogenesis and visceral fat expansion. These findings uncover a fundamental mechanism of age-dependent adipose remodeling, offering critical insights into age-related metabolic diseases.

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Resolving p53 to Create Clinically-Relevant Mutation Models

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Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada 2023年第1期29卷 1087-1090页

作者： Solares, Maria J. Jonaid, G.M. Kelly, Deborah F. Molecular Cellular Integrative Biosciences Graduate Program Huck Institutes of the Life Sciences Pennsylvania State University University Park PA United States Department of Biomedical Engineering Pennsylvania State University University Park PA United States Center for Structural Oncology Pennsylvania State University University Park PA United States Bioinformatics and Genomics Graduate Program Huck Institutes of the Life Sciences Pennsylvania State University University Park PA United States

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ASpli: integrative analysis of splicing landscapes through RNA-Seq assays (Mar, btab141, 2021)

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bioinformatics 2021年第12期37卷 1783-1783页

作者： Mancini, Estefania Rabinovich, Andres Iserte, Javier Yanovsky, Marcelo Chernomoretz, Ariel Gene Regulation Stem Cells and Cancer Program Centre for Genomic Regulation (CRG) The Barcelona Institute of Science and Technology Barcelona Spain Integrative Systems Biology Fundacion Instituto Leloir Buenos Aires Argentina Instituto de Investigaciones Bioquímicas de Buenos Aires Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Buenos Aires Argentina DStructural Bioinformatics Fundacion Instituto Leloir Buenos Aires Argentina Comparative Genomics of Plant Development Fundacion Instituto Leloir Buenos Aires Argentina

Motivation Genome-wide analysis of alternative splicing has been a very active field of research since the early days of next generation sequencing technologies. Since then, ever-growing data availability and the development of increasingly sophisticated analysis methods have uncovered the complexity of the general splicing repertoire. A large number of splicing analysis methodologies exist, each of them presenting its own strengths and weaknesses. For instance, methods exclusively relying on junction information do not take advantage of the large majority of reads produced in an RNA-seq assay, isoform reconstruction methods might not detect novel intron retention events, some solutions can only handle canonical splicing events, and many existing methods can only perform pairwise *** In this contribution, we present ASpli, a computational suite implemented in R statistical language, that allows the identification of changes in both, annotated and novel alternative-splicing events and can deal with simple, multi-factor or paired experimental designs. Our integrative computational workflow, that considers the same GLM model applied to different sets of reads and junctions, allows computation of complementary splicing signals. Analyzing simulated and real data, we found that the consolidation of these signals resulted in a robust proxy of the occurrence of splicing alterations. While the analysis of junctions allowed us to uncover annotated as well as non-annotated events, read coverage signals notably increased recall capabilities at a very competitive performance when compared against other state-of-the-art splicing analysis *** and implementation ASpli is freely available from the Bioconductor project site https://***/doi:10.18129/*** information Supplementary data are available at bioinformatics online.

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