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      A critical role of nuclear m6A reader YTHDC1 in leukemogenesis by regulating MCM complex–mediated DNA replication

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          Abstract

          YTHDC1 has distinct functions as a nuclear N6-methyladenosine (m6A) reader in regulating RNA metabolism. Here we show that YTHDC1 is overexpressed in acute myeloid leukemia (AML) and that it is required for the proliferation and survival of human AML cells. Genetic deletion of Ythdc1 markedly blocks AML development and maintenance as well as self-renewal of leukemia stem cells (LSCs) in vivo in mice. We found that Ythdc1 is also required for normal hematopoiesis and hematopoietic stem and progenitor cell (HSPC) maintenance in vivo. Notably, Ythdc1 haploinsufficiency reduces self-renewal of LSCs but not HSPCs in vivo. YTHDC1 knockdown has a strong inhibitory effect on proliferation of primary AML cells. Mechanistically, YTHDC1 regulates leukemogenesis through MCM4, which is a critical regulator of DNA replication. Our study provides compelling evidence that shows an oncogenic role and a distinct mechanism of YTHDC1 in AML.

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          NIH Image to ImageJ: 25 years of image analysis

          Kevin W Eliceiri, Caroline A Schneider, Wayne S Rasband (2019)
          For the past twenty five years the NIH family of imaging software, NIH Image and ImageJ have been pioneers as open tools for scientific image analysis. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.
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            GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis

            Zefang Tang, Boxi Kang, Chenwei Li … (2019)
            Abstract Introduced in 2017, the GEPIA (Gene Expression Profiling Interactive Analysis) web server has been a valuable and highly cited resource for gene expression analysis based on tumor and normal samples from the TCGA and the GTEx databases. Here, we present GEPIA2, an updated and enhanced version to provide insights with higher resolution and more functionalities. Featuring 198 619 isoforms and 84 cancer subtypes, GEPIA2 has extended gene expression quantification from the gene level to the transcript level, and supports analysis of a specific cancer subtype, and comparison between subtypes. In addition, GEPIA2 has adopted new analysis techniques of gene signature quantification inspired by single-cell sequencing studies, and provides customized analysis where users can upload their own RNA-seq data and compare them with TCGA and GTEx samples. We also offer an API for batch process and easy retrieval of the analysis results. The updated web server is publicly accessible at http://gepia2.cancer-pku.cn/.
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              Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.

              Dan Dominissini, Sharon Moshitch-Moshkovitz, Schraga Schwartz … (2012)
              An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA, but it remains largely uncharted territory. Although biochemical studies indicate that N(6)-methyladenosine (m(6)A) is the most prevalent internal modification in messenger RNA, an in-depth study of its distribution and functions has been impeded by a lack of robust analytical methods. Here we present the human and mouse m(6)A modification landscape in a transcriptome-wide manner, using a novel approach, m(6)A-seq, based on antibody-mediated capture and massively parallel sequencing. We identify over 12,000 m(6)A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in two distinct landmarks--around stop codons and within long internal exons--and are highly conserved between human and mouse. Although most sites are well preserved across normal and cancerous tissues and in response to various stimuli, a subset of stimulus-dependent, dynamically modulated sites is identified. Silencing the m(6)A methyltransferase significantly affects gene expression and alternative splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. Our findings therefore suggest that RNA decoration by m(6)A has a fundamental role in regulation of gene expression.
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                Author and article information

                Contributors
                Journal
                Title: Blood
                Publisher: American Society of Hematology
                ISSN (Print): 0006-4971
                ISSN (Electronic): 1528-0020
                Publication date Created: December 30 2021
                Publication date (Print): December 30 2021
                Volume: 138
                Issue: 26
                Pages: 2838-2852
                Affiliations
                [1 ]Department of Medicine, UF Health Cancer Center, University of Florida, Gainesville, FL;
                [2 ]Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL;
                [3 ]Howard Hughes Medical Institute, The University of Chicago, Chicago, IL;
                [4 ]Division of Infectious Disease, Department of Pediatrics, University of Florida, Gainesville, FL;
                [5 ]Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA;
                [6 ]Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, China;
                [7 ]State Key Laboratory of Reproductive Medicine, Center for Global Health, Gusu School, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China;
                [8 ]Department of Medicine, University of Virginia, Charlottesville, VA; and
                [9 ]Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL
                Article
                DOI: 10.1182/blood.2021011707
                PubMed ID: 34255814
                SO-VID: e19988e6-e0cd-4c33-becf-906c286df072
                Copyright © © 2021
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