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Nucleic Acids Research Advance Access published online on March 20, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp127
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gene Regulation, Chromatin, and Epigenetics

Promoter targeted small RNAs induce long-term transcriptional gene silencing in human cells

Peter G. Hawkins1,2, Sharon Santoso1, Christopher Adams3, Vasiliki Anest3 and Kevin V. Morris1,*

1Department of Molecular and Experimental Medicine, 2Kellogg School of Science and Technology, The Scripps Research Institute, TPC-19 10550, N. Torrey Pines Road, La Jolla, CA, 92037 and 3Division of Epigenetics, Invitrogen Corporation, 1600 Faraday Ave, Carlsbad, CA 92008, USA

*To whom correspondence should be addressed: Tel: +1 858 784 9949; Fax: +1 858 784 2131; Email: kmorris{at}scripps.edu

Received December 22, 2008. Revised February 12, 2009. Accepted February 16, 2009.

Small RNAs targeted to gene promoters in human cells can mediate transcriptional gene silencing (TGS) by directing silent state epigenetic modifications to targeted loci. Many mechanistic details of this process remain poorly defined, and the ability to stably modulate gene expression in this manner has not been explored. Here we describe the mechanisms of establishment and maintenance of long-term transcriptional silencing of the human ubiquitin C gene (UbC). Sustained targeting of the UbC promoter with a small RNA for a minimum of 3 days resulted in long-term silencing which correlated with an early increase in histone methylation and a later increase in DNA methylation at the targeted locus. Transcriptional silencing of UbC required the presence of a promoter-associated RNA. The establishment and maintenance of the TGS were shown to require distinct protein factors. Argonaute 1 (Ago1), DNA methyltransferase 3a (DNMT3a) and histone deacetylase 1 (HDAC1) were required for the initiation of silencing, and DNA methyltransferase 1 (DNMT1) was necessary for maintenance. Taken together the data presented here highlight the cellular pathway with which noncoding RNAs interact to epigenetically regulate gene expression in human cells.


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