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Clonal hematopoiesis landscape in frequent blood donors

Blood 2025年第21期145卷 2411-2423页

作者： Karpova, Darja Huerga Encabo, Hector Donato, Elisa Calderazzo, Silvia Scherer, Michael Llorian-Sopena, Miriam Leppä, Aino-Maija Würth, Roberto Stelmach, Patrick Papazoglou, Despoina Ferrelli, Alessandra Ngo, Steven Kotova, Iuliia Harenkamp, Sabine Zimmer, Kai Wolf, Dominik Panten, Jasper Reed, John Przybylla, Adriana Tonn, Torsten Kopp-Schneider, Annette Velten, Lars DiPersio, John F. Wong, Terrence N. Bonnet, Dominique Bonig, Halvard Trumpp, Andreas Division of Stem Cells and Cancer German Cancer Research Center Heidelberg Germany Heidelberg Institute for Stem Cell Technology and Experimental Medicine Heidelberg Germany German Cancer Consortium Heidelberg Germany Division of Oncology Department of Medicine Washington University School of Medicine St. Louis MO Institute for Transfusion Medicine and Immunohematology Goethe University Hospital Medical School German Red Cross Blood Donor Service Frankfurt Germany Hematopoietic Stem Cell Laboratory The Francis Crick Institute London United Kingdom Division of Biostatistics German Cancer Research Center Heidelberg Germany Computational Biology and Health Genomics Centre for Genomic Regulation Barcelona Institute of Science and Technology Barcelona Spain Division of Cancer Epigenomics German Cancer Research Centre Heidelberg Germany Bioinformatics and Biostatistics The Francis Crick Institute London United Kingdom European Molecular Biology Laboratory Hamburg Germany Department of Internal Medicine V Hematology and Oncology Comprehensive Cancer Center Innsbruck Medical University of Innsbruck Innsbruck Austria VASCage–Centre on Clinical Stroke Research Innsbruck Austria Division of Regulatory Genomics and Cancer Evolution German Cancer Research Center Heidelberg Germany Division of Cancer Biology Department of Medicine University of Michigan Medical School Ann Arbor MI United States

Donor blood saves lives, yet the potential impact of recurrent large-volume phlebotomy on donor health and hematopoietic stem cells (HSCs) remains largely unexplored. In our study, we conducted a comprehensive screening of 217 older male volunteer donors with a history of extensive blood donation (>100 lifetime donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FDs) compared with sporadic donors (<10 lifetime donations;212 donors). However, upon deeper analysis of mutations in DNMT3A, the most commonly affected gene in CH, we observed distinct mutational patterns between the FD and age/sex-matched control donor cohorts. Functional analysis of FD-enriched DNMT3A variants examined in CRISPR-edited human HSCs demonstrated their competitive outgrowth potential upon stimulation with erythropoietin (EPO), a hormone that increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with interferon gamma. Through concurrent mutational and immunophenotypic profiling of primary samples at single-cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, whereas no significant lineage bias was observed in HSCs harboring EPO-responsive DNMT3A variants. The latter exhibited preferential erythroid differentiation when persistent erythropoietic stress was applied to CRISPR-edited human HSC xenografts. Our data demonstrate a nuanced, ongoing Darwinian evolution at the somatic stem cell level, with EPO identified as a novel environmental factor that favors HSCs carrying certain DNMT3A mutations. © 2025 American Society of Hematology

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Deletion of a single CTCF motif at the boundary of a chromatin domain with three FGF genes disrupts gene expression and embryonic development

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Developmental Cell 2025年

作者： Chakraborty, Shreeta Wenzlitschke, Nina Anderson, Matthew J. Eraso, Ariel Baudic, Manon Thompson, Joyce J. Evans, Alicia A. Shatford-Adams, Lilly M. Chari, Raj Awasthi, Parirokh Dale, Ryan K. Lewandoski, Mark Petros, Timothy J. Rocha, Pedro P. Unit on Genome Structure and Regulation National Institute of Child Health and Human Development National Institutes of Health Bethesda 20892 MD United States Genetics of Vertebrate Development Section Cancer and Developmental Biology Laboratory National Cancer Institute National Institutes of Health Frederick 21702 MD United States Bioinformatics and Scientific Programming Core National Institute of Child Health and Human Development National Institutes of Health Bethesda 20892 MD United States Laboratory Animal Sciences Program Frederick National Laboratory for Cancer Research Frederick 21702 MD United States Unit on Cellular and Molecular Neurodevelopment National Institute of Child Health and Human Development National Institutes of Health Bethesda 20892 MD United States National Cancer Institute NIH Bethesda 20892 MD United States

Chromatin domains delimited by CTCF can restrict the range of enhancer action. However, disruption of some domain boundaries results in mild gene dysregulation and phenotypes. We tested whether perturbing a domain with multiple developmental regulators would lead to more severe outcomes. We chose a domain with three FGF ligand genes—Fgf3, Fgf4, and Fgf15—that control different murine developmental processes. Heterozygous deletion of a 23.9-kb boundary defined by four CTCF sites led to ectopic interactions of the FGF genes with enhancers active in the brain and induced FGF expression. This caused orofacial clefts, encephalocele, and fully penetrant perinatal lethality. Loss of the single CTCF motif oriented toward the enhancers—but not the three toward the FGF genes—recapitulated these phenotypes. Our works shows that small sequence variants at particular domain boundaries can have a surprisingly outsized effect and must be considered as potential sources of gene dysregulation in development and disease. © 2025

关键词： CTCF epigenetics FGF gene regulation nuclear organization

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A multi-disciplinary approach to study the biological role of miRNA in deep-branching unicellular flagellates

A multi-disciplinary approach to study the biological role o...

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2011国际基因组学大会

作者： Petrus Tang Po-Jung Huang Shih-Chieh Chen Bioinformatics Center Chang Gung UniversityTaoyuanTaiwan Molecular Regulation&Bioinformatics Laboratory Dept.of ParasitologyChang Gung UniversityTaiwan Molecular Regulation & Bioinformatics Laboratory Dept.of ParasitologyChang Gung UniversityTaiwan

MicroRNAs(miRNAs) are a class of extensively studied small RNA population that plays a critical role in eukaryotic gene ***,very little is known about the regulation of miRNA in *** explore the evolutionary origins of... 详细信息

关键词： miRNA A multi-disciplinary approach to study the biological role of miRNA in deep-branching unicellular flagellates miRNAs

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A multi-disciplinary approach to study the biological role of miRNA in deep-branching unicellular flagellates

A multi-disciplinary approach to study the biological role o...

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2011·国际基因组学大会

作者： Petrus Tang Po-Jung Huang Wei-Chen Lin Shih-Chieh Chen Yong-Han Lin Bioinformatics Center Chang Gung University Taoyuan Taiwan Molecular Regulation & Bioinformatics Laboratory Dept.of Parasitology Chang Gung University Taiwan Bioinformatics Center Chang Gung University Taoyuan Taiwan Molecular Regulation & Bioinformatics Laboratory Dept.of Parasitology Chang Gung University Taiwan

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Exploring the sequence determinants of amyloid structure using position-specific scoring matrices (vol 7, pg 237, 2010)

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NATURE METHODS 2010年第10期7卷 855-855页

作者： Maurer-Stroh, Sebastian Debulpaep, Maja Kuemmerer, Nico de la Paz, Manuela Lopez Martins, Ivo Cristiano Reumers, Joke Morris, Kyle L. Copland, Alastair Serpell, Louise Serrano, Luis Schymkowitz, Joost W. H. Rousseau, Frederic VIB SWITCH Laboratory Flanders Institute for Biotechnology and Vrije Universiteit Brussel Brussels Belgium. Bioinformatics Institute (BII) Agency for Science Technology and Research (ASTAR) Singapore. Structures Programme European Molecular Biology Laboratory Heidelberg Germany. Department of Chemistry School of Life Sciences University of Sussex Falmer Brighton UK. Systems Biology Programme Centre for Genomic Regulation Barcelona Spain.

Protein aggregation results in β-sheet–like assemblies that adopt either a variety of amorphous morphologies or ordered amyloid-like structures. These differences in structure also reflect biological differences; amyloid and amorphous β-sheet aggregates have different chaperone affinities, accumulate in different cellular locations and are degraded by different mechanisms. Further, amyloid function depends entirely on a high intrinsic degree of order. Here we experimentally explored the sequence space of amyloid hexapeptides and used the derived data to build Waltz, a web-based tool that uses a position-specific scoring matrix to determine amyloid-forming sequences. Waltz allows users to identify and better distinguish between amyloid sequences and amorphous β-sheet aggregates and allowed us to identify amyloid-forming regions in functional amyloids.

关键词： bioinformatics Protein aggregation Protein structure predictions

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Pilot Survey of Expressed Sequence Tags (EST) from Trichomonas vaginalis

Pilot Survey of Expressed Sequence Tags (EST) from Trichomon...

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12th International Congress of Protozoology

作者： Petrus Tang ChengHsun Chiu JyhWei Shin Rose Lin Weimin Hsu Sara Yu-Hsin Cheng Chun-Hsien Chen Ying-Shiung Lee Molecular Regulation and Bioinformatics Laboratory Department of Parasitology Chang Gung University Taoyuan 333 Taiwan Chang Gung Bioinformatics Center Taoyuan 333 Taiwan Chang Gung Molecular Infectious Diseases Research Center Chang Gung Memorial Hospital Taoyuan 333 Taiwan Department of Parasitology Medical College National Cheng Kung University No. 1 Dashiue Road 701 Dung Chiu Tainan Taiwan Molecular Regulation and Bioinformatics Laboratory Department of Parasitology Chang Gung University Taoyuan 333 Taiwan Molecular Regulation and Bioinformatics Laboratory Department of Parasitology Chang Gung University Taoyuan 333 Taiwan Chang Gung Bioinformatics Center Taoyuan 333 Taiwan Department of Information Management College of Management Chang Gung University Taoyuan 333 Taiwan Medical Genomic Center Chang Gung Memorial Hospital Taoyuan 333 Taiwan

A Trichomonas vaginalis expressed sequence tag (TvEST) project is being carried out to generate and analysis 60,000 ESTs. A pilot survey was conducted on 26,571 randomly selected EST clones from normal, cold-stressed and G2M arrested cDNA libraries. Assembling and clustering of the single-pass sequence from the 5' end of amplified cDNAs resulted in 2938 contigs and 6170 singletons. Around 70% of the unique ESTs can be matched to the hypothetical open reading frames predicted by the TIGR T. vaginalis genome project. On the basis of BLAST search, about 35% of the ESTs exhibited similarity with known proteins or motifs/domains. Novel genes related to cell growth, metabolism and pathogenesis

关键词： EST Pilot Survey of Expressed Sequence Tags from Trichomonas vaginalis

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Epitranscriptomic technologies and analyses

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Science China(Life Sciences) 2020年第4期63卷 501-515页

作者： Xiaoyu Li Qiao-Xia Liang Jin-Ran Lin Jinying Peng Jian-Hua Yang Chengqi Yi Yang Yu Qiangfeng Cliff Zhang Ke-Ren Zhou State Key Laboratory of Protein and Plant Gene Research School of Life SciencesPeking UniversityBeijing 100871China MOE Key Laboratory of Gene Function and Regulation State Key Laboratory for BiocontrolSchool of Life SciencesSun Yat-Sen UniversityGuangzhou 510275China The Fifth Affiliated Hospital Sun Yat-Sen UniversityZhuhai 519000China Department of Chemical Biology and Synthetic and Functional Biomolecules Center College of Chemistry and Molecular EngineeringPeking UniversityBeijing 100871China Key Laboratory of RNA Biology CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101 China MOE Key Laboratory of Bioinformatics Beijing Advanced Innovation Center for Structural BiologyCenter for Synthetic and Systems BiologyTsinghua-Peking Joint Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China

RNA can interact with RNA-binding proteins(RBPs),mRNA,or other non-coding RNAs(ncRNAs)to form complex regulatory ***-throughput CLIP-seq,degradome-seq,and RNA-RNA interactome sequencing methods represent powerful approaches to identify biologically relevant ncRNA-target and protein-ncRNA ***,assigning ncRNAs to their regulatory target genes or interacting RNA-binding proteins(RBPs)remains technically *** modifications to mRNA also play important roles in regulating gene *** of the functional roles of these modifications relies highly on the detection methods *** structure is also critical at nearly every step of the RNA life *** this review,we summarize recent advances and limitations in CLIP technologies and discuss the computational challenges of and bioinformatics tools used for decoding the functions and regulatory networks of *** also summarize methods used to detect RNA modifications and to probe RNA structure.

关键词： ncRNA bioinformatics CLIP-seq RNA modification quantification and locus-specific detection methods transcriptome-wide sequencing technologies RNA structuromes RNA structure probing methods

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Identification of microRNA in the protist Trichomonas vaginalis

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Genomics 2009年第5期93卷 487-493页

作者： Lin, Wei-Chen Li, Sung-Chou Lin, Wen-Chang Shin, Jyh-Wei Hu, Song-Nian Yu, Xiao-Min Huang, Ting-Yun Chen, Shih-Chieh Chen, Hua-Chien Chen, Shu-Jen Huang, Po-Jung Ruei-Chi Gan, Richie Chiu, Cheng-Hsun Tang, Petrus Molecular Regulation and Bioinformatics Laboratory Chang Gung University Taoyuan 333 Taiwan Division of Microbiology Graduate Institute of Biomedical Sciences Chang Gung University Taoyuan 333 Taiwan Institute of Biomedical Informatics National Yang-Ming University Taipei 112 Taiwan Taiwan International Graduate Program in Bioinformatics Academia Sinica Taipei 115 Taiwan Institute of Biomedical Sciences Academia Sinica Taipei 115 Taiwan Department of Parasitology National Cheng Kung University Tainan 701 Taiwan Key Laboratory of Genome Sciences and Information Beijing Institute of Genomics Chinese Academy of Sciences Beijing China Graduate University Chinese Academy of Sciences Beijing China Department of Life Sciences Chang Gung University Taoyuan 333 Taiwan Molecular Medicine Research Center Chang Gung University Taoyuan 333 Taiwan Bioinformatics Center Chang Gung University Tao-Yuan 333 Taiwan Chang Gung Molecular Infectious Diseases Research Center Chang Gung Memorial Hospital Taoyuan 333 Taiwan

MicroRNAs (miRNAs) are a class of small noncoding RNAs that have important regulatory roles in multicellular organisms. However, miRNA has never been identified experimentally in protist. Direct cloning of 438 expressed miRNA tags by microRNA serial analysis of gene expression from the parasitic protist Trichomonas vaginalis identified nine candidate miRNAs. bioinformatics analysis of the corresponding genomic region revealed that these miRNA candidates contain a classical stem-loop-stem structure of pre-microRNAs. Analysis of the 20 nt long mature tva-miR-001 showed that it is an intergenic miRNA located at the scaffold DS113596. Tva-miR-001 was differentially expressed in the trophozoite, pseudocyst and amoeboid stages. Based on the experimental results of the present study, we provided solid evidence that protist possesses a miRNA regulating network comparable with multicellular organisms for the first time. © 2009 Elsevier Inc. All rights reserved.

关键词： MicroRNA Protist Trichomonas vaginalis

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0414 Recurrent chimeric transcripts in human and mouseGet access

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Journal of Animal Science 2016年第SUPPL_5期94卷 200–201页

作者： Djebali, S. Rodríguez Martín, B. Palumbo, E. Pervouchine, D. D. Breschi, A. Davis, C. Dobin, A. Alonso, G. Rastrojo, A. Aguado, B. Gingeras, T. R. Guigó, R. GenPhySE INRA Castanet-Tolosan France Universitat Pompeu Fabra (UPF) Barcelona Spain Bioinformatics and Genomics Program Centre for Genomic Regulation (CRG) Barcelona Spain Cold Spring Harbor Laboratory Functional Genomics NY Centro de Biología Molecular Severo Ochoa (CSIC- UAM) Madrid Spain

The formation of chimeric transcripts (chimeras) has been widely reported. Some of them reflect underlying chromosomal rearrangements, or are the results of the propensity of reverse transcriptase to engage in template switching, however, a proportion of cases genuinely appear to correspond totrans-splicing of RNAs, as has previously been *** we use ENCODE and mouse ENCODE deeply sequenced and bio-replicated RNaseq data from 18 human and 30 mouse samples, and the ChimPipe program, to identify chimeras occurring in multiple biological samples (recurrent), and between the same pairs of genes in human and mouse, since they are more likely to be transcriptionally induced and *** common chimeras tend to connect gene pairs located on the same chromosome and relatively near to each other ( < 100kb), therefore pointing to polymerase read-through, however interchromosomal chimeras are also observed, pointing totrans-splicing. Importantly, these recurrent chimeras tend to maintain an open reading frame, and could therefore generate chimeric proteins. We also observe that not only the gene-to-gene connection is conserved, but strikingly so are specific junction sites. The genes connected in common chimeras tend to be involved in morphogenesis and body plan formation, and consistently tend to be detected in cell lines of embryonic *** of human chimeras by RT-PCR yielded a success rate of 50%, and subsequent cloning and sequencing revealed novel transcript structures, of which some preserve the domains from the two parent genes. Applying this method to multiple animal species and breeds will help us understanding chimera evolution as well as reveal some links between genotype and phenotype.

关键词： chimeras transcripts trans-splicing

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Image Data Resource: a bioimage data integration and publication platform (vol 14, pg 775, 2017)

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NATURE METHODS 2018年第11期15卷 984-984页

作者： Williams, Eleanor Moore, Josh Li, Simon W. Rustici, Gabriella Tarkowska, Aleksandra Chessel, Anatole Leo, Simone Antal, Balint Ferguson, Richard K. Sarkans, Ugis Brazma, Alvis Salas, Rafael E. Carazo Swedlow, Jason R. Centre for Gene Regulation and Expression University of Dundee Dundee UK Division of Computational Biology University of Dundee Dundee UK European Molecular Biology Laboratory European Bioinformatics Institute Hinxton UK Pharmacology Department University of Cambridge Cambridge UK Genetics Department University of Cambridge Cambridge UK Cambridge Systems Biology Centre University of Cambridge Cambridge UK LOB Ecole Polytechnique CNRS INSERM Université Paris-Saclay Palaiseau France Center for Advanced Studies Research and Development in Sardinia (CRS4) Pula Italy School of Cell and Molecular Medicine University of Bristol Bristol UK

This paper was originally published under standard Nature America Inc. copyright. As of the date of this correction, the Resource is available online as an open-access paper with a CC-BY license. No other part of the ...

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