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DNMT1-interacting RNAs block gene-specific DNA methylation

机译：DNMT1相互作用的RNA阻断基因特异性DNA甲基化

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摘要

DNA甲基化是与基因表达的沉默相关的一种表观遗传修饰。Daniel Tenen及同事提出，活性转录直接调控DNA甲基化的水平。来自被研究很透彻的甲基化敏感基因CfSRA的一个非编码RNA与DNA甲基转移酶DNMT1相互作用，阻止在CEBPA位点上的甲基化，从而帮助表达。DNMT1和RNAs之间的功能联系似乎发生在无数基因位点上。这些发现支持认为非编码RNA通过与DNMT1相互作用来参与基因组甲基化模式的调控的假说，同时也为异常DNA甲基化的点特异性改变提出了一个潜在治疗策略。%DNA methylation was first described almost a century ago; however, the rules governing its establishment and maintenance remain elusive. Here we present data demonstrating that active transcription regulates levels of genomic methylation. We identify a novel RNA arising from the CEBPA gene locus that is critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extend the generality of this finding to numerous gene loci. Collectively, these results delineate the nature of DNMT1 -RNA interactions and suggest strategies for gene-selective demethylation of therapeutic targets in human diseases.
机译：DNA甲基化是与基因表达的沉默相关的一种表观遗传修饰。Daniel Tenen及同事提出，活性转录直接调控DNA甲基化的水平。来自被研究很透彻的甲基化敏感基因CfSRA的一个非编码RNA与DNA甲基转移酶DNMT1相互作用，阻止在CEBPA位点上的甲基化，从而帮助表达。DNMT1和RNAs之间的功能联系似乎发生在无数基因位点上。这些发现支持认为非编码RNA通过与DNMT1相互作用来参与基因组甲基化模式的调控的假说，同时也为异常DNA甲基化的点特异性改变提出了一个潜在治疗策略。%DNA methylation was first described almost a century ago; however, the rules governing its establishment and maintenance remain elusive. Here we present data demonstrating that active transcription regulates levels of genomic methylation. We identify a novel RNA arising from the CEBPA gene locus that is critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extend the generality of this finding to numerous gene loci. Collectively, these results delineate the nature of DNMT1 -RNA interactions and suggest strategies for gene-selective demethylation of therapeutic targets in human diseases.

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  • 来源
    《Nature》 |2013年第7476期|371-376a3|共7页
  • 作者

    Annalisa Di Ruscio; Alexander K. Ebralidze; Touati Benoukraf; Giovanni Amabile; Loyal A. Goff; Jolyon Terragni; Maria Eugenia Figueroa; Lorena Lobo De Figueiredo Pontes; Meritxell Alberich-Jorda; Pu Zhang; Mengchu Wu; Francesco DAlo; Ari Melnick; Giuseppe Leone; Konstantin K. Ebralidze; Sriharsa Pradhan; John L. Rinn; Daniel G. Tenen;

  • 作者单位

    Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA,Universita Cattolica del Sacro Cuore, Institute of Hematology, L.go A. Gemelli 8, Rome 00168, Italy;

    Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA;

    Cancer Science Institute, National University of Singapore, 117599, Singapore;

    Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA;

    Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA,Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge, Massachusetts 02139, USA;

    New England Biolabs, 240 County Road, Ipswich, Massachusetts 01938-2723, USA;

    University of Michigan, Department of Pathology, Ann Arbor, Michigan 48109-2200, USA;

    Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA;

    Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA,Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 142 20 Prague, Czech Republic;

    Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Cancer Science Institute, National University of Singapore, 117599, Singapore;

    Universita Cattolica del Sacro Cuore, Institute of Hematology, L.go A. Gemelli 8, Rome 00168, Italy;

    Department of Medicine, Hematology-Oncology, C-620 Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA;

    Universita Cattolica del Sacro Cuore, Institute of Hematology, L.go A. Gemelli 8, Rome 00168, Italy;

    Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA;

    New England Biolabs, 240 County Road, Ipswich, Massachusetts 01938-2723, USA;

    Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA,Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA,Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,Cancer Science Institute, National University of Singapore, 117599, Singapore;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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