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Changing the public perception of human embryology ( vol 25, pg 1717, 2023)

NATURE CELL biology 2023年第12期25卷 1884-1884页

作者： Rivron, Nicolas C. Martinez-Arias, Alfonso Sermon, Karen Mummery, Christine Scholer, Hans R. Wells, James Nichols, Jenny Hadjantonakis, Anna-Katerina Lancaster, Madeline A. Moris, Naomi Fu, Jianping Sturmey, Roger G. Niakan, Kathy Rossant, Janet Kato, Kazuto Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) Vienna BioCenter (VBC) Vienna Austria Systems Bioengineering MELIS Universidad Pompeu Fabra and Catalan Institution for Research and Advanced Studies (ICREA) Barcelona Spain Research Group Reproduction and Genetics Vrije Universiteit Brussel Brussels Belgium European Society for Human Reproduction and Embryology (ESHRE) Strombeek-Bever Belgium Leiden University Medical Center Leiden the Netherlands Max Planck Institute for Molecular Biomedicine Münster Germany Center for Stem Cell and Organoid Medicine Cincinnati Children’s Hospital Medical Center Cincinnati OH USA Division of Developmental Biology Cincinnati Children’s Hospital Medical Center Cincinnati OH USA MRC Human Genetics Unit Institute of Genetics and Cancer The University of Edinburgh Crewe Road Edinburgh UK Developmental Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA MRC Laboratory of Molecular Biology Cambridge UK The Francis Crick Institute London UK Department of Mechanical Engineering University of Michigan Ann Arbor MI USA Department of Biomedical Engineering University of Michigan Ann Arbor MI USA Department of Cell & Developmental Biology University of Michigan Medical School Ann Arbor MI USA Biomedical Institute for Multimorbidity Hull York Medical School University of Hull Hull UK Cambridge Reproduction University of Cambridge Cambridge UK The Centre for Trophoblast Research Department of Physiology Development and Neuroscience University of Cambridge Cambridge UK Human Embryo and Stem Cell Laboratory The Francis Crick Institute London UK Wellcome Trust–Medical Research Council Stem Cell Institute University of Cambridge Jeffrey Cheah Biomedical Centre Cambridge UK Epigenetics Programme Babraham Institute Cambridge UK The Hospital for Sick Children Toronto ON Canada Department of Biomedical Ethics and Public Policy Graduate School of Medicin

Human embryology is flourishing thanks to an impetus provided by embryo models formed from stem cells. These scientific advances require meticulous experimental work and a refined ethical framework, but also sensible ... 详细信息

关键词： Embryology Embryonic stem cells

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Transcriptional Control of HP1a By the RNA Binding Proteins Rbmx/L1 Maintain Chromatin State in Myeloid Leukemia

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BLOOD 2020年 136卷 15-15页

作者： Nguyen, Diu T. T. Prieto, Camila Liu, Zhaoqi Wheat, Justin Perez, Alexendar Gourkanti, Saroj Chou, Timothy Barin, Ersilia Chow, Arthur Taggart, James Hoskova, Katerina Dhodapkar, Meera Schurer, Alexandra Barlowe, Trevor Stephen Vu, Ly Leslie, Christina Steidl, Ulrich G. Rabadan, Raul Kharas, Michael G. Memorial Sloan Kettering Cancer Center New York NY Department of Systems Biology Columbia University New York NY Albert Einstein College of Medicine New York Molecular Pharmacology Program Memorial Sloan Kettering Cancer Center New York NY University of Chicago Chicago Dartmouth Geisel School of Medicine Hanover NH Simon Fraser University Vancouver Canada Computational Biology Program Memorial Sloan Kettering Cancer Center New York NY Hematology/Oncology Montefiore Medical Center/Albert Einstein College of Medicine Bronx NY Molecular Pharmacology Memorial Sloan Kettering Cancer Center New York NY

Mutations and aberrant expression of RNA binding proteins (RBPs) have recently been found to contribute to leukemia development (Prieto and Kharas, CSH, 2020). Previously we have identified the RBP RBMX (RNA binding motif protein, X-linked) in our shRNA in vivo screen using murine MLL-AF9 driven leukemia (Prieto et al, ASH abstract 2018). Here we uncover the role of RBMX and its retrogene RBMXL1 in normal hematopoiesis and leukemogenesis in mouse and human systems. To investigate RBMX function in normal hematopoiesis, we created an Rbmx Mx1-Cre conditional knockout model to specifically delete Rbmx in the hematopoietic system. We gender stratified our studies since Rbmx is sex-linked. Deletion of Rbmx in both female and male primary mice as well as in non-competitive transplant animals did not affect hematopoiesis. Additionally, Rbmx knockout (KO) leads to a mild reduction in multipotent progenitors (MPP2 and MPP4) in female competitive transplanted mice although no defects in long-term hematopoiesis was observed in male competitive transplanted mice. These data suggest that Rbmx is dispensable for normal hematopoiesis. To identify the role of RBMX in leukemogenesis we knockout Rbmx in MLL-AF9 murine leukemia cells and found it significantly reduced colony formation in vitro and delayed leukemogenesis in vivo , indicating that Rbmx is required for leukemia maintenance. We observed, however, that MLL-AF9 transformed cells from Rbmx KO donor mice showed no delay in leukemia initiation versus cells from wildtype. We then determined that while Rbmx deletion is effective with complete depletion of mRNA, the retrogene RBMXL1 expression is maintained in Rbmx deficient cells, which may compensate for Rbmx deletion in leukemia initiation. Indeed, depletion of RBMXL1 by shRNAs (KD) in Rbmx deficient leukemia cells results in a drastic reduction in colony formation, increased colony myeloid differentiation, and induced apoptosis in cells deficient for both RBMXL1 and RBMX comp

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Genome and clonal hematopoiesis stability contrasts with immune,cfDNA,mitochondrial,and telomere length changes during short duration spaceflight

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Precision Clinical Medicine 2024年第1期7卷 1-13页

作者： J.Sebastian Garcia-Medina Karolina Sienkiewicz S.Anand Narayanan Eliah G.Overbey Kirill Grigorev Krista A.Ryon Marissa Burke Jacqueline Proszynski Braden Tierney Caleb M.Schmidt Nuria Mencia-Trinchant Remi Klotz Veronica Ortiz Jonathan Foox Christopher Chin Deena Najjar Irina Matei Irenaeus Chan Carlos Cruchaga Ashley Kleinman JangKeun Kim Alexander Lucaci Conor Loy Omary Mzava Iwijn De Vlaminck Anvita Singaraju Lynn E.Taylor Julian C.Schmidt Michael A.Schmidt Kelly Blease Juan Moreno Andrew Boddicker Junhua Zhao Bryan Lajoie Andrew Altomare Semyon Kruglyak Shawn Levy Min Yu Duane C.Hassane Susan M.Bailey Kelly Bolton Jaime Mateus Christopher E.Mason Department of Physiology and Biophysics Weill Cornell MedicineCornell UniversityNew YorkNY 10021USA The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine Weill Cornell MedicineNew YorkNY 10021USA Department of Immunology Weill Cornell MedicineCornell UniversityNew YorkNY 10021USA Department of Stem Cell Biology and Regenerative Medicine Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Space Exploration Technologies Corporation HawthomeCA 90250USA Sovaris Aerospace BoulderCO 80302USA Advanced Pattern Analysis&Human Performance Group BoulderCO 80302USA Children's Cancer and Blood Foundation Laboratories Departments of Pediatrics and Cell and Developmental BiologyDrukier Institute for Children's HealthMeyer Cancer CenterWeill Cornell MedicineNew YorkNY 10021USA Meyer Cancer Center Weill Cornell MedicineNew YorkNY 10065USA Department of Nutrition and Integrative Physiology Florida State UniversityTallahasseeFL 32306USA Department of Systems Engineering Colorado State UniversityFort CollinsCO 80523USA Element Biosciences San DiegoCA 10055USA Department of Environmental and Radiological Health Sciences Colorado State UniversityFort CollinsCO 80523USA Cell and Molecular Biology Program Colorado State UniversityFort CollinsCO 80523USA BioAstra Inc New YorkNYUSA Washington University St Louis Oncology Division St.LouisMO 63100USA Meinig School of Biomedical Engineering Cornell UniversityIthacaNY 14853USA The Feil Family Brain and Mind Research Institute Weill Cornell MedicineNY 10021USA WorldQuant Initiative for Quantitative Prediction Weill Cornell MedicineNew YorkNY 10021USA

Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic *** advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation *** To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA *** length was measured by quantitative PCR,while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations.A robust bioinformatic pipeline was used for data analysis,including variant calling to assess mutational *** Telomere elongation occurred during spaceflight and shortened after return to ***-free DNA analysis revealed increased immune cell signatures *** significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was *** long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months *** Our findings provide valuable insights into the physiological consequences of short-duration spaceflight,with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to *** sequencing data will serve as a reference point for studying the early development of CHIP in astronauts,an understudied phenomenon as previous studies have focused on career *** study will serve as a reference point for future commercial and non-commercial spaceflight,low Earth orbit(LEO)missions,and deep-space exploration.

关键词： genomes clonal hematopoiesis stability immune mitochondria ribosomes spaceflight

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Subcytoplasmic Location of Translation Controls Protein Output

SSRN

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SSRN 2022年

作者： Horste, Ellen L. Zhen, Gang Fansler, Mervin M. Chen, Xiuzhen Lee, Flora C.Y. Ule, Jernej Mayr, Christine Gerstner Sloan Kettering Graduate School of Biomedical Sciences New YorkNY10065 United States Cancer Biology and Genetics Program Sloan Kettering Institute New YorkNY10065 United States Tri-Institutional Training Program in Computational Biology and Medicine Weill-Cornell Graduate College New YorkNY10021 United States UK Dementia Research Institute King's College London LondonSE5 9NU United Kingdom The Francis Crick Institute 1 Midland Road LondonNW1 1AT United Kingdom

The cytoplasm is highly compartmentalized, but the extent of subcytopIasmic mRNA localization in non-polarized cells is largely unknown. We used fluorescent particle sorting to determine mRNA enrichment in three unenclosed cytoplasmic compartments: the canonicaI rough endopIasmic reticuIum (CRER), the TIS granule-associated rough endopIasmic reticuIum (TGER), and the cytosol. Focusing our analysis on non-membrane protein-encoding mRNAs, we observed that 53% have a unique subcytoplasmic localization pattern which is determined by a combinatorial code of 3′UTR-bound RNA-binding proteins. Compartment-enriched mRNAs differed in production and degradation rates and the expression levels and functional classes of their encoded proteins. The TGER domain enriches mRNAs that encode transcription factors, the CRER highly expressed proteins, and the cytosol unstable mRNAs. The rough ER environment is stimulatory as redirecting cytosolic mRNAs to the ER increases their protein expression by two-fold, independently of the bound RNA-binding proteins. We show that local translation environments functionally compartmentaIize the *** Information: This work was funded by the NIH Director′s Pioneer Award (DP1-GM123454), the R35GM144046 NIH grant, a grant from the Pershing Square Sohn cancer Research Alliance, a grant from the G. Harold and Leila Y. Mathers Foundation, and the MSK Core Grant (P30 CA008748) to CM. J.U. received funding from the ERC under the European Union Horizon 2020 Research and Innovation program (835300-RNPdynamics) and The Francis Crick Institute receives its core funding from cancer Research UK (CC0102), the UK Medical Research Council (CC0102), and the Wellcome Trust (CC0102). An NIH F31 (CA254335-01) fellowship was awarded to *** of Interests: The authors declare no competing interests. © 2022, The Authors. All rights reserved.

关键词： Proteins

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Cell phenotypic transition proceeds through concerted reorganization of gene regulatory network

arXiv

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arXiv 2021年

作者： Wang, Weikang Poe, Dante Ni, Ke Xing, Jianhua Department of Computational and Systems Biology University of Pittsburgh PittsburghPA15232 United States Joint CMU-Pitt Ph.D. Program in Computational Biology University of Pittsburgh PittsburghPA United States Department of Physics and Astronomy University of Pittsburgh PittsburghPA15232 United States UPMC-Hillman Cancer Center University of Pittsburgh PittsburghPA United States

Phenotype transition takes place in many biological processes such as differentiation, and understanding how a cell reprograms its global gene expression profile is a problem of rate theories. A cell phenotype transition accompanies with switching of expression rates of clusters of genes, analogous to domain flipping in an Ising system. Here through analyzing single cell RNA sequencing data in the framework of transition path theory, we set to study how such a genome-wide expression program switching proceeds in three different cell transition processes. For each process after reconstructing a Markov transition model in the cell state space, we formed an ensemble of shortest paths connecting the initial and final cell states, reconstructed a reaction coordinate describing the transition progression, and inferred the gene regulation network (GRN) along the reaction coordinate. In all three processes we observed common pattern that the frustration of gene regulatory network (GRN), defined as overall confliction between the regulation received by genes and their expression states, first increases then decreases when approaching a new phenotype. The results support a mechanism of concerted silencing of genes that are active in the initial phenotype and activation of genes that are active in the final phenotype. © 2021, CC BY.

关键词： Ising model

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Author Correction: ChromaFold predicts the 3D contact map from single-cell chromatin accessibility

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Nature communications 2025年第1期16卷 684页

作者： Vianne R Gao Rui Yang Arnav Das Renhe Luo Hanzhi Luo Dylan R McNally Ioannis Karagiannidis Martin A Rivas Zhong-Min Wang Darko Barisic Alireza Karbalayghareh Wilfred Wong Yingqian A Zhan Christopher R Chin William S Noble Jeff A Bilmes Effie Apostolou Michael G Kharas Wendy Béguelin Aaron D Viny Danwei Huangfu Alexander Y Rudensky Ari M Melnick Christina S Leslie Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY USA. Tri-Institutional Program in Computational Biology and Medicine New York NY USA. University of Washington Seattle WA USA. Developmental Biology Program Sloan Kettering Institute New York NY USA. Molecular Pharmacology Program Experimental Therapeutics Center and Center for Stem Cell Biology Memorial Sloan Kettering Cancer Center New York NY USA. Caryl and Israel Englander Institute for Precision Medicine Institute for Computational Biomedicine Weill Cornell Medicine Cornell University New York NY USA. Division of Hematology and Medical Oncology Department of Medicine Weill Cornell Medical College New York NY USA. Department of Biochemistry & Molecular Biology Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine Miami FL USA. Howard Hughes Medical Institute and Immunology Program Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center New York NY USA. Center for Epigenetics Research Memorial Sloan Kettering Cancer Center New York NY USA. Joan and Sanford I. Weill Department of Medicine Sandra and Edward Meyer Cancer Center Weill Cornell Medicine New York NY USA. Departments of Medicine Division of Hematology & Oncology and of Genetics & Development Columbia Stem Cell Initiative Herbert Irving Comprehensive Cancer Center Columbia University Irving Medical Center New York NY USA. Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY USA. lesliec@***.

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KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection

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Science (New York, N.Y.) 2025年第6735期387卷 eadn2337页

作者： Fagerberg, Eric Attanasio, John Dien, Christine Singh, Jaiveer Kessler, Emily A. Abdullah, Leena Shen, Jian Hunt, Brian G. Connolly, Kelli A. De Brouwer, Edward He, Jiaming Iyer, Nivedita R. Buck, Jessica Borr, Emily R. Damo, Martina Foster, Gena G. Giles, Josephine R. Huang, Yina H. Tsang, John S. Krishnaswamy, Smita Cui, Weiguo Joshi, Nikhil S. Department of Immunobiology Yale University School of Medicine New Haven CT United States Program in Computational Biology & Bioinformatics Yale University New Haven CT United States Department of Microbiology and Immunology Geisel School of Medicine at Dartmouth NH United States Department of Pathology Feinberg School of Medicine at Northwestern University Chicago IL United States Department of Genetics and Computer Science Yale University School of Medicine New Haven CT United States Department of Medicine University of Chicago Chicago IL United States Section of Hematology Department of Internal Medicine Yale University School of Medicine New Haven CT United States Department of Systems Pharmacology and Translational Therapeutics University of Pennsylvania Philadelphia PA United States Institute for Immunology Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Parker Institute for Cancer Immunotherapy Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Yale Center for Systems and Engineering Immunology Yale University School of Medicine New Haven CT United States New Haven CT United States Department of Biomedical Engineering Yale University New Haven CT United States Computational Biology and Bioinformatics Program Yale University CT USA New Haven United States Applied Math Program Yale University New Haven CT United States

Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9-based perturbation sequencing to assess the role of ~40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.

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Assessing Engraftment Following Fecal Microbiota Transplant

arXiv

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arXiv 2024年

作者： Herman, Chloe Barker, Bridget M. Bartelli, Thais F. Chandra, Vidhi Krajmalnik-Brown, Rosa Jewell, Mary Li, Le Liao, Chen McAllister, Florencia Nirmalkar, Khemlal Xavier, Joao B. Caporaso, J. Gregory Pathogen and Microbiome Institute Northern Arizona University FlagstaffAZ United States School of Informatics Computing and Cyber Systems Northern Arizona University FlagstaffAZ United States Department of Clinical Cancer Prevention University of Texas MD Anderson Cancer Center HoustonTX United States Biodesign Center for Health Through Microbiomes Arizona State University TempeAZ United States School of Sustainable Engineering and the Built Environment Arizona State University TempeAZ United States Independent author Salt Lake CityUT United States Program for Computational and Systems Biology Memorial Sloan-Kettering Cancer Center New YorkNY United States Department of Gastrointestinal Medical Oncology University of Texas MD Anderson Cancer Center HoustonTX United States Department of Immunology The University of Texas MD Anderson Cancer Center HoustonTX United States Department of Biological Sciences Northern Arizona University FlagstaffAZ United States

Fecal Microbiota Transplant (FMT) is an FDA approved treatment for recurrent Clostridium difficile infections, and is being explored for other clinical applications, from alleviating digestive and neurological disorders, to priming the microbiome for cancer treatment, and restoring microbiomes impacted by cancer treatment. Quantifying the extent of engraftment following an FMT is important in determining if a recipient didn’t respond because the engrafted microbiome didn’t produce the desired outcomes (a successful FMT, but negative treatment outcome), or the microbiome didn’t engraft (an unsuccessful FMT and negative treatment outcome). The lack of a consistent methodology for quantifying FMT engraftment extent hinders the assessment of FMT success and its relation to clinical outcomes, and presents challenges for comparing FMT results and protocols across studies. Here we review 46 studies of FMT in humans and model organisms and group their approaches for assessing the extent to which an FMT engrafts into three criteria: 1) Chimeric Asymmetric Community Coalescence investigates microbiome shifts following FMT engraftment using methods such as alpha diversity comparisons, beta diversity comparisons, and microbiome source tracking. 2) Donated Microbiome Indicator Features tracks donated microbiome features (e.g., amplicon sequence variants or species of interest) as a signal of engraftment with methods such as differential abundance testing based on the current sample collection, or tracking changes in feature abundances that have been previously identified (e.g., from FMT or disease-relevant literature). 3) Temporal Stability examines how resistant post-FMT recipient’s microbiomes are to reverting back to their baseline microbiome. Individually, these criteria each highlight a critical aspect of microbiome engraftment;investigated together, however, they provide a clearer assessment of microbiome engraftment. We discuss the pros and cons of each of these criteria,

关键词： Diseases

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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries (vol 55, pg 89, 2023)

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NATURE genetics 2023年第3期55卷 519-520页

作者： Fernandez-Rozadilla, Ceres Timofeeva, Maria Chen, Zhishan Law, Philip Thomas, Minta Schmit, Stephanie Diez-Obrero, Virginia Hsu, Li Fernandez-Tajes, Juan Palles, Claire Sherwood, Kitty Briggs, Sarah Svinti, Victoria Donnelly, Kevin Farrington, Susan Blackmur, James Vaughan-Shaw, Peter Shu, Xiao-ou Long, Jirong Cai, Qiuyin Guo, Xingyi Lu, Yingchang Broderick, Peter Studd, James Huyghe, Jeroen Harrison, Tabitha Conti, David Dampier, Christopher Devall, Mathew Schumacher, Fredrick Melas, Marilena Rennert, Gad Obon-Santacana, Mireia Martin-Sanchez, Vicente Moratalla-Navarro, Ferran Oh, Jae Hwan Kim, Jeongseon Jee, Sun Ha Jung, Keum Ji Kweon, Sun-Seog Shin, Min-Ho Shin, Aesun Ahn, Yoon-Ok Kim, Dong-Hyun Oze, Isao Wen, Wanqing Matsuo, Keitaro Matsuda, Koichi Tanikawa, Chizu Ren, Zefang Gao, Yu-Tang Jia, Wei-Hua Hopper, John Jenkins, Mark Win, Aung Ko Pai, Rish Figueiredo, Jane Haile, Robert Gallinger, Steven Woods, Michael Newcomb, Polly Duggan, David Cheadle, Jeremy Kaplan, Richard Maughan, Timothy Kerr, Rachel Kerr, David Kirac, Iva Bohm, Jan Mecklin, Lukka-Pekka Jousilahti, Pekka Knekt, Paul Aaltonen, Lauri Rissanen, Harri Pukkala, Eero Eriksson, Johan Cajuso, Tatiana Hanninen, Ulrika Kondelin, Johanna Palin, Kimmo Tanskanen, Tomas Renkonen-Sinisalo, Laura Zanke, Brent Mannisto, Satu Albanes, Demetrius Weinstein, Stephanie Ruiz-Narvaez, Edward Palmer, Julie Buchanan, Daniel Platz, Elizabeth Visvanathan, Kala Ulrich, Cornelia Siegel, Erin Brezina, Stefanie Gsur, Andrea Campbell, Peter Chang-Claude, Jenny Hoffmeister, Michael Brenner, Hermann Slattery, Martha Potter, John Tsilidis, Konstantinos Schulze, Matthias Gunter, Marc Murphy, Neil Castells, Antoni Castellvi-Bel, Sergi Moreira, Leticia Arndt, Volker Shcherbina, Anna Stern, Mariana Pardamean, Bens Bishop, Timothy Giles, Graham Southey, Melissa Idos, Gregory McDonnell, Kevin Abu-Ful, Zomoroda Greenson, Joel Shulman, Katerina Lejbkowicz, Flavio Offit, Kenneth Su, Yu-Ru Steinfelder, Robert Keku, Temitope van Guelpen, Bethany Hudson, Thomas Hampel, Heather Pearlman, Edinburgh Cancer Research Centre Institute of Genomics and Cancer University of Edinburgh Edinburgh UK Genomic Medicine Group Instituto de Investigacion Sanitaria de Santiago Santiago de Compostela Spain Colon Cancer Genetics Group Medical Research Council Human Genetics Unit Institute of Genetics and Cancer University of Edinburgh Edinburgh UK Danish Institute for Advanced Study Department of Public Health University of Southern Denmark Odense Denmark Division of Epidemiology Department of Medicine Vanderbilt-Ingram Cancer Center Vanderbilt Epidemiology Center Vanderbilt University Medical Center Nashville TN USA Division of Genetics and Epidemiology Institute of Cancer Research London UK Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA USA Genomic Medicine Institute Cleveland Clinic Cleveland OH USA Population and Cancer Prevention Program Case Comprehensive Cancer Center Cleveland OH USA Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute Barcelona Spain Oncology Data Analytics Program Catalan Institute of Oncology Barcelona Spain Consortium for Biomedical Research in Epidemiology and Public Health Madrid Madrid Spain Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain Department of Biostatistics School of Public Health University of Washington Seattle WA USA Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham UK Department of Public Health Richard Doll Building University of Oxford Oxford UK Department of Biomedical Informatics Vanderbilt University School of Medicine Nashville TN USA Department of Preventive Medicine USC Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles CA USA Center for Public Health Genomics Department of Public Health Sciences University of Virginia Charlottesville VA USA Department of Populat

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

关键词： Colorectal cancer Epigenomics Genome-wide association studies Transcriptomics

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The mTORC1 complex in pre-osteoblasts regulates whole-body energy metabolism independently of osteocalcin

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Bone Research 2021年第1期9卷 109-125页

作者： Pawanrat Tangseefa Sally K.Martin Peck Yin Chin James Breen Chui Yan Mah Paul A.Baldock Gary A.Wittert Amanda J.Page Christopher G.Proud Stephen Fitter Andrew C.W.Zannettino Adelaide Medical School Faculty of Health and Medical ScienceUniversity of AdelaideAdelaide5005 SAAustralia Cancer Program Precision Medicine ThemeSouth Australian Health and Medical Research InstituteAdelaide5000 SAAustralia Research Centre for Reproductive Health School of Paediatrics and Reproductive HealthUniversity of AdelaideAdelaide5005 SAAustralia Computational&Systems Biology program Precision Medicine ThemeSouth Australian Health and Medical Research InstituteAdelaide5000 SAAustralia Robinson Research Institute University of AdelaideAdelaideSA 5005Australia Bioinformatics Hub University of AdelaideAdelaideSA 5005Australia Freemasons Foundation Centre for Men’s Health University of AdelaideAdelaide5005 SAAustralia Skeletal Metabolism Group Garvan Institute of Medical ResearchSydney2010 NSWAustralia Nutrition Diabetes&Metabolism ProgramLifelong Health ThemeSouth Australian Health and Medical Research InstituteAdelaide5000 SAAustralia School of Biological Sciences University of AdelaideAdelaide5005 SAAustralia Central Adelaide Local Health Network AdelaideSAAustralia

Overnutrition causes hyperactivation of mTORC1-dependent negative feedback loops leading to the downregulation of insulin signaling and development of insulin *** osteoblasts(OBs),insulin signaling plays a crucial role in the control of systemic glucose *** utilized mice with conditional deletion of Rptor to investigate how the loss of mTORC1 function in OB affects glucose metabolism under normal and overnutrition dietary *** to the controls,chow-fed Rptorob−/−mice had substantially less fat mass and exhibited adipocyte ***,upon feeding with high-fat diet,mice with pre-and post-natal deletion of Rptor in OBs were protected from diet-induced obesity and exhibited improved glucose metabolism with lower fasting glucose and insulin levels,increased glucose tolerance and insulin *** leanness and resistance to weight gain was not attributable to changes in food intake,physical activity or lipid absorption but instead was due to increased energy expenditure and greater whole-body substrate ***-seq revealed an increase in glycolysis and skeletal insulin signaling pathways,which correlated with the potentiation of insulin signaling and increased insulin-dependent glucose uptake in Rptorknockout ***,these findings point to a critical role for the mTORC1 complex in the skeletal regulation of wholebody glucose metabolism and the skeletal development of insulin resistance.

关键词： metabolism mTORC1 homeostasis

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