Dnmt1-interacting rnas block gene-specific dna methylation

ABSTRACT 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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS NON-CANONICAL FUNCTIONS OF UHRF1 MAINTAIN DNA METHYLATION HOMEOSTASIS IN CANCER

CELLS Article Open access 05 April 2024 THE CONCURRENCE OF DNA METHYLATION AND DEMETHYLATION IS ASSOCIATED WITH TRANSCRIPTION REGULATION Article Open access 06 September 2021 RNA M6A

REGULATES TRANSCRIPTION VIA DNA DEMETHYLATION AND CHROMATIN ACCESSIBILITY Article 07 September 2022 ACCESSION CODES ACCESSIONS GENE EXPRESSION OMNIBUS * GSE32153 * GSE32162 * GSE32168 *

GSE32260 * GSE41279 DATA DEPOSITS Sequencing and microarray data sets are available for download at Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/projects/geo/) under

the following accession numbers: microarray expression, GSE32153; RIPseq, GSE32162; RRBS, GSE32168; and RNAseq, GSE41279. The accession number for the project is GSE32260. REFERENCES *

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ACKNOWLEDGEMENTS This work was supported by grants CA118316, CA66996 and HL56745 from the National Institutes of Health (NIH) to D.G.T., the Italian Foundation for Cancer Research (FIRC)

‘Leonino Fontana e Maria Lionello’ fellowship, the NIH T32 HL007917-11A1 and the Società Italiana di Ematologia Sperimentale (SIES) ‘Dr.Tito Bastianello’ fellowship to A.D.R.; FAMRI CIA

(103063) grant to A.K.E.; Fondazione Roma ‘Progetto cellule staminali’ to G.L. and F.D’A.; the American Italian Cancer Foundation Fellowship (AICF) to G.A.; Fundação de Amparo à Pesquisa do

Estado de São Paulo (FAPESP)—grant no. 2011/11822-6—to L.L.D.F.P.; the National Research Foundation and the Singapore Ministry of Education under its Centres of Excellence initiative to M.W.

and T.B.; the MSMT Navrat grant LK21307 to M.A.-J. S.P. and J.T. were supported by New England Biolabs. We thank R. White, D. Johnson, M. Frank-Kamenetskii, S. M. Mirkin, D. Gautheret, B.

Tazon-Vega, C. Bonifer, C. Bock, M. T. Voso, J. J. Dunn (deceased) and R. A. M. Fouchier for helpful advice and reagents; I. Rigoutsos for providing the latest released pyknons database; all

the members of the Tenen Laboratory; P. Tan and T. S. Ting from the Genome Institute of Singapore; R. Soong from the Cancer Science Institute Translational Interface; J. LaVecchio and G.

Buruzula from the Harvard Stem Cell Institute/Joslin Diabetes Center flow cytometry facility; and F. Hyde from Epicentre-Illumina. This research is supported by the Singapore Ministry of

Health’s National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award (D.G.T.). AUTHOR INFORMATION Author notes * Annalisa Di Ruscio and Alexander

K. Ebralidze: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Harvard Stem Cell Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA Annalisa Di

Ruscio, Alexander K. Ebralidze, Giovanni Amabile, Lorena Lobo De Figueiredo Pontes, Meritxell Alberich-Jorda, Pu Zhang, John L. Rinn & Daniel G. Tenen * Beth Israel Deaconess Medical

Center, Boston, 02115, Massachusetts, USA Annalisa Di Ruscio, Alexander K. Ebralidze, Giovanni Amabile, Lorena Lobo De Figueiredo Pontes, Meritxell Alberich-Jorda, Konstantin K. Ebralidze 

& John L. Rinn * Università Cattolica del Sacro Cuore, Institute of Hematology, L.go A. Gemelli 8, Rome 00168, Italy, Annalisa Di Ruscio, Francesco D’Alò & Giuseppe Leone * Cancer

Science Institute, National University of Singapore, 117599, Singapore, Touati Benoukraf, Mengchu Wu & Daniel G. Tenen * Department of Stem Cell and Regenerative Biology, Harvard

University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA, Loyal A. Goff & John L. Rinn * Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, 02142,

Massachusetts, USA Loyal A. Goff & John L. Rinn * Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge,

Massachusetts 02139, USA, Loyal A. Goff * New England Biolabs, 240 County Road, Ipswich, 01938-2723, Massachusetts, USA Jolyon Terragni & Sriharsa Pradhan * Department of Pathology,

University of Michigan, Ann Arbor, 48109-2200, Michigan, USA Maria Eugenia Figueroa * Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 142 20 Prague, Czech

Republic, Meritxell Alberich-Jorda * Department of Medicine, Hematology-Oncology, C-620 Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA, Ari Melnick Authors *

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Scholar CONTRIBUTIONS D.G.T. supervised the project; A.D.R., A.K.E. and D.G.T. conceived and designed the study; A.D.R., A.K.E., G.A., P.Z., M.A.-J., F.D’A., S.P., L.L.D.F.P. and J.T.

performed experiments; M.W. performed sequencing and microarray experiments; T.B. and L.A.G. analysed RIP-seq, RNA-seq, RRBS and microarray data; M.E.F. and A.M. performed the MassARRAY

experiment and assisted in the analysis; A.D.R., A.K.E., G.L., K.K.E., J.L.R. and D.G.T. wrote the paper. CORRESPONDING AUTHOR Correspondence to Daniel G. Tenen. ETHICS DECLARATIONS

COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file contains Supplementary Results, Supplementary Methods,

Supplementary References and Supplementary Figures 1-6. (PDF 4040 kb) SUPPLEMENTARY DATA 1 This file contains the MassARRAY primer sets. (XLS 46 kb) SUPPLEMENTARY DATA 2 This file contains

a list of gene loci belonging to DNMT1-bound and unbound groups along with respective expression and DNA methylation levels. (XLS 2680 kb) SUPPLEMENTARY DATA 3 This file contains a full list

of Biological Process Gene Ontology terms significantly enriched in cluster C. (XLS 250 kb) POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR

FIG. 3 POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR FIG. 5 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Di Ruscio, A., Ebralidze, A., Benoukraf,

T. _et al._ DNMT1-interacting RNAs block gene-specific DNA methylation. _Nature_ 503, 371–376 (2013). https://doi.org/10.1038/nature12598 Download citation * Received: 13 November 2011 *

Accepted: 21 August 2013 * Published: 09 October 2013 * Issue Date: 21 November 2013 * DOI: https://doi.org/10.1038/nature12598 SHARE THIS ARTICLE Anyone you share the following link with

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