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  • 1
    Publication Date: 2012-05-12
    Description: 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dominissini, Dan -- Moshitch-Moshkovitz, Sharon -- Schwartz, Schraga -- Salmon-Divon, Mali -- Ungar, Lior -- Osenberg, Sivan -- Cesarkas, Karen -- Jacob-Hirsch, Jasmine -- Amariglio, Ninette -- Kupiec, Martin -- Sorek, Rotem -- Rechavi, Gideon -- England -- Nature. 2012 Apr 29;485(7397):201-6. doi: 10.1038/nature11112.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22575960" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/*analogs & derivatives/*genetics ; Alternative Splicing ; Animals ; Base Sequence ; Cell Line, Tumor ; Conserved Sequence ; Evolution, Molecular ; Hep G2 Cells ; Humans ; *Metabolome/genetics ; Methylation ; Methyltransferases/deficiency/genetics/metabolism ; Mice ; RNA/genetics/*metabolism ; RNA, Ribosomal/genetics/metabolism ; RNA, Transfer/genetics/metabolism ; RNA-Binding Proteins/metabolism ; Transcriptome/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-05-07
    Description: MicroRNAs (miRNAs) show differential expression across breast cancer subtypes, and have both oncogenic and tumour-suppressive roles. Here we report the miRNA expression profiles of 1,302 breast tumours with matching detailed clinical annotation, long-term follow-up and genomic and messenger RNA expression data. This provides a comprehensive overview of the quantity, distribution and variation of the miRNA population and provides information on the extent to which genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture, suggesting an important role for post-transcriptional regulation. The key clinical parameters and cellular pathways related to the miRNA landscape are characterized, revealing context-dependent interactions, for example with regards to cell adhesion and Wnt signalling. Notably, only prognostic miRNA signatures derived from breast tumours devoid of somatic copy-number aberrations (CNA-devoid) are consistently prognostic across several other subtypes and can be validated in external cohorts. We then use a data-driven approach to seek the effects of miRNAs associated with differential co-expression of mRNAs, and find that miRNAs act as modulators of mRNA-mRNA interactions rather than as on-off molecular switches. We demonstrate such an important modulatory role for miRNAs in the biology of CNA-devoid breast cancers, a common subtype in which the immune response is prominent. These findings represent a new framework for studying the biology of miRNAs in human breast cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dvinge, Heidi -- Git, Anna -- Graf, Stefan -- Salmon-Divon, Mali -- Curtis, Christina -- Sottoriva, Andrea -- Zhao, Yongjun -- Hirst, Martin -- Armisen, Javier -- Miska, Eric A -- Chin, Suet-Feung -- Provenzano, Elena -- Turashvili, Gulisa -- Green, Andrew -- Ellis, Ian -- Aparicio, Sam -- Caldas, Carlos -- 11832/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2013 May 16;497(7449):378-82. doi: 10.1038/nature12108. Epub 2013 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23644459" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Breast Neoplasms/*genetics/pathology ; DNA Copy Number Variations ; Female ; Follow-Up Studies ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Genome, Human/genetics ; Humans ; Kaplan-Meier Estimate ; MicroRNAs/*genetics/metabolism ; Prognosis ; Proportional Hazards Models ; RNA, Messenger/genetics/metabolism ; RNA, Neoplasm/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2015-01-09
    Description: Naive and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an N(6)-methyladenosine (m(6)A) transferase, as a regulator for terminating murine naive pluripotency. Mettl3 knockout preimplantation epiblasts and naive embryonic stem cells are depleted for m(6)A in mRNAs, yet are viable. However, they fail to adequately terminate their naive state and, subsequently, undergo aberrant and restricted lineage priming at the postimplantation stage, which leads to early embryonic lethality. m(6)A predominantly and directly reduces mRNA stability, including that of key naive pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence naive and primed pluripotency in an opposing manner.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geula, Shay -- Moshitch-Moshkovitz, Sharon -- Dominissini, Dan -- Mansour, Abed AlFatah -- Kol, Nitzan -- Salmon-Divon, Mali -- Hershkovitz, Vera -- Peer, Eyal -- Mor, Nofar -- Manor, Yair S -- Ben-Haim, Moshe Shay -- Eyal, Eran -- Yunger, Sharon -- Pinto, Yishay -- Jaitin, Diego Adhemar -- Viukov, Sergey -- Rais, Yoach -- Krupalnik, Vladislav -- Chomsky, Elad -- Zerbib, Mirie -- Maza, Itay -- Rechavi, Yoav -- Massarwa, Rada -- Hanna, Suhair -- Amit, Ido -- Levanon, Erez Y -- Amariglio, Ninette -- Stern-Ginossar, Noam -- Novershtern, Noa -- Rechavi, Gideon -- Hanna, Jacob H -- New York, N.Y. -- Science. 2015 Feb 27;347(6225):1002-6. doi: 10.1126/science.1261417. Epub 2015 Jan 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. ; Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. ; Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. ; Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. ; The Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. ; The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. The Department of Pediatrics and the Pediatric Immunology Unit, Rambam Medical Center, and the B. Rappaport Faculty of Medicine, Technion, Haifa, Israel. ; Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. ; The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. jacob.hanna@weizmann.ac.il noa.novershtern@weizmann.ac.il gidi.rechavi@sheba.health.gov.il. ; Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. jacob.hanna@weizmann.ac.il noa.novershtern@weizmann.ac.il gidi.rechavi@sheba.health.gov.il.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25569111" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/*analogs & derivatives/metabolism ; Animals ; Blastocyst/enzymology ; Cell Differentiation/genetics/*physiology ; Cell Line ; Embryo Loss/genetics ; Epigenesis, Genetic ; Female ; Gene Knockout Techniques ; Male ; Methylation ; Methyltransferases/genetics/*physiology ; Mice ; Mice, Knockout ; Pluripotent Stem Cells/*cytology/enzymology ; RNA, Messenger/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2016-02-11
    Description: Gene expression can be regulated post-transcriptionally through dynamic and reversible RNA modifications. A recent noteworthy example is N(6)-methyladenosine (m(6)A), which affects messenger RNA (mRNA) localization, stability, translation and splicing. Here we report on a new mRNA modification, N(1)-methyladenosine (m(1)A), that occurs on thousands of different gene transcripts in eukaryotic cells, from yeast to mammals, at an estimated average transcript stoichiometry of 20% in humans. Employing newly developed sequencing approaches, we show that m(1)A is enriched around the start codon upstream of the first splice site: it preferentially decorates more structured regions around canonical and alternative translation initiation sites, is dynamic in response to physiological conditions, and correlates positively with protein production. These unique features are highly conserved in mouse and human cells, strongly indicating a functional role for m(1)A in promoting translation of methylated mRNA.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dominissini, Dan -- Nachtergaele, Sigrid -- Moshitch-Moshkovitz, Sharon -- Peer, Eyal -- Kol, Nitzan -- Ben-Haim, Moshe Shay -- Dai, Qing -- Di Segni, Ayelet -- Salmon-Divon, Mali -- Clark, Wesley C -- Zheng, Guanqun -- Pan, Tao -- Solomon, Oz -- Eyal, Eran -- Hershkovitz, Vera -- Han, Dali -- Dore, Louis C -- Amariglio, Ninette -- Rechavi, Gideon -- He, Chuan -- GM113194/GM/NIGMS NIH HHS/ -- GM71440/GM/NIGMS NIH HHS/ -- HG006699/HG/NHGRI NIH HHS/ -- HG008688/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Feb 25;530(7591):441-6. doi: 10.1038/nature16998. Epub 2016 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA. ; Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA. ; Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. ; Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. ; Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA. ; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863196" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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