Article abstract
Nature Chemical Biology 1, 216 - 222 (2005)
Published online: 31 July 2005 | doi:10.1038/nchembio725
Inhibiting gene expression at transcription start sites in chromosomal DNA with antigene RNAs
Bethany A Janowski1,2, Kenneth E Huffman1,2, Jacob C Schwartz1,2, Rosalyn Ram1,2, Daniel Hardy2, David S Shames1,3,4, John D Minna1,3,4 & David R Corey1,2
Abstract
Transcription start sites are critical switches for converting recognition of chromosomal DNA into active synthesis of RNA. Their functional importance suggests that they may be ideal targets for regulating gene expression. Here, we report potent inhibition of gene expression by antigene RNAs (agRNAs) complementary to transcription start sites within human chromosomal DNA. Silencing does not require methylation of DNA and differs from all known mechanisms for inhibiting transcription. agRNAs overlap DNA sequences within the open complex formed by RNA polymerase, and silencing is acutely sensitive to single base shifts. agRNAs effectively silence both TATA-less and TATA-box-containing promoters. Transcription start sites occur within every gene, providing predictable targets for agRNAs. Potent inhibition of multiple genes suggests that agRNAs may represent a natural mechanism for controlling transcription, may complement siRNAs and miRNAs that target mRNA, and will be valuable agents for silencing gene expression.
- Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
- Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
- Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
- The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Correspondence to: David R Corey1,2 e-mail: david.corey@utsouthwestern.edu
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