Research

DNMT1-interacting RNAs block gene-specific DNA methylation (Nature, Oct 2013)

DNA methylation is a process in which certain building blocks of DNA, the genetic code, are chemically modified without resulting in a change in the code itself. As such, it is considered an epigenetic modification. DNA methylation was first described almost a century ago, but the rules governing its establishment and maintenance remain elusive. DNA methylation is associated with silencing of gene expression and found in many diseases. For example, in cancer, it is often the case that genes called tumor suppressors, which inhibit tumor formation, are silenced in the cancer cells, and this is associated with DNA methylation. However, whether methylation of the DNA silences genes, or whether DNA methylation follows gene shut-off (and perhaps enforces silencing), is not clear. In this study in press in Nature (under embargo, likely will go online mid to late October), we present data demonstrating that active gene expression (“transcription” resulting in production of RNA) regulates levels of genomic methylation. We focused on a novel noncoding RNA in a specific tumor suppressor, CEBPA. This noncoding RNA is critical in regulating the local DNA methylation profile. We also demonstrate that this RNA binds to DNA methyl transferase 1 (DNMT1), the enzyme that methylates DNA, and prevents methylation of the CEBPA gene. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression studies demonstrates that this principle extends to thousands, if not all, genes. Furthermore, our results suggest strategies for gene-selective demethylation of therapeutic targets in human diseases such as cancer.

Authors:

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

*These authors contributed equally to this work.

1Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
2Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
3Policlinico A. Gemelli, Catholic University,School of Medicine and Surgery,Rome 00168, Italy.
4Cancer Science Institute, National University of Singapore, 117599, Singapore.
5Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
6Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
7Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge, Massachusetts 02139, USA.
8New England Biolabs, 240 County Road, Ipswich, Massachusetts 01938-2723,USA.
9University of Michigan, Department of Pathology, Ann Arbor, Michigan 48109-2200, USA.
10Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 142 20 Prague, Czech Republic.
11Department of Medicine, Hematology-Oncology, C-620 Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, USA