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Effect of chemical modifications on modulation of gene expression by duplex antigene RNAs that are complementary to non-coding transcripts at gene promoters

Effect of chemical modifications on modulation of gene expression by duplex antigene RNAs that are complementary to non-coding transcripts at gene promoters
Effect of chemical modifications on modulation of gene expression by duplex antigene RNAs that are complementary to non-coding transcripts at gene promoters
Antigene RNAs (agRNAs) are small RNA duplexes that target non-coding transcripts rather than mRNA and specifically suppress or activate gene expression in a sequence-dependent manner. For many applications in vivo, it is likely that agRNAs will require chemical modification. We have synthesized agRNAs that contain different classes of chemical modification and have tested their ability to modulate expression of the human progesterone receptor gene. We find that both silencing and activating agRNAs can retain activity after modification. Both guide and passenger strands can be modified and functional agRNAs can contain 2?F-RNA, 2?OMe-RNA, and locked nucleic acid substitutions, or combinations of multiple modifications. The mechanism of agRNA activity appears to be maintained after chemical modification: both native and modified agRNAs modulate recruitment of RNA polymerase II, have the same effect on promoter-derived antisense transcripts, and must be double-stranded. These data demonstrate that agRNA activity is compatible with a wide range of chemical modifications and may facilitate in vivo applications.
0305-1048
5242-5259
Watts, Jonathan K.
c4de85ee-aaa3-4e7d-99b3-147a4de4f01c
Yu, Dongbo
e7923a0e-9af4-45bc-865b-a33a49e4a1e3
Charisse, Klaus
4c06dfab-de9e-4d5f-aaf0-092c1c84eaa2
Montaillier, Christophe
87e45ef7-91ad-4902-91b9-ac59524c815b
Potier, Pierre
51497c94-887d-4a17-b863-260702a70e42
Manoharan, Muthiah
27339e16-ddf9-4b73-8eb9-cfaa53075065
Corey, David R.
ce328d93-1c07-4ab0-952c-da300f6738f9
Watts, Jonathan K.
c4de85ee-aaa3-4e7d-99b3-147a4de4f01c
Yu, Dongbo
e7923a0e-9af4-45bc-865b-a33a49e4a1e3
Charisse, Klaus
4c06dfab-de9e-4d5f-aaf0-092c1c84eaa2
Montaillier, Christophe
87e45ef7-91ad-4902-91b9-ac59524c815b
Potier, Pierre
51497c94-887d-4a17-b863-260702a70e42
Manoharan, Muthiah
27339e16-ddf9-4b73-8eb9-cfaa53075065
Corey, David R.
ce328d93-1c07-4ab0-952c-da300f6738f9

Watts, Jonathan K., Yu, Dongbo, Charisse, Klaus, Montaillier, Christophe, Potier, Pierre, Manoharan, Muthiah and Corey, David R. (2010) Effect of chemical modifications on modulation of gene expression by duplex antigene RNAs that are complementary to non-coding transcripts at gene promoters. Nucleic Acids Research, 38 (15), 5242-5259. (doi:10.1093/nar/gkq258).

Record type: Article

Abstract

Antigene RNAs (agRNAs) are small RNA duplexes that target non-coding transcripts rather than mRNA and specifically suppress or activate gene expression in a sequence-dependent manner. For many applications in vivo, it is likely that agRNAs will require chemical modification. We have synthesized agRNAs that contain different classes of chemical modification and have tested their ability to modulate expression of the human progesterone receptor gene. We find that both silencing and activating agRNAs can retain activity after modification. Both guide and passenger strands can be modified and functional agRNAs can contain 2?F-RNA, 2?OMe-RNA, and locked nucleic acid substitutions, or combinations of multiple modifications. The mechanism of agRNA activity appears to be maintained after chemical modification: both native and modified agRNAs modulate recruitment of RNA polymerase II, have the same effect on promoter-derived antisense transcripts, and must be double-stranded. These data demonstrate that agRNA activity is compatible with a wide range of chemical modifications and may facilitate in vivo applications.

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Published date: 2010
Organisations: Chemistry, Organic Chemistry: SCF

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Local EPrints ID: 342428
URI: http://eprints.soton.ac.uk/id/eprint/342428
ISSN: 0305-1048
PURE UUID: 98b5d642-6102-4e4c-8e7a-7252eb45822f

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Date deposited: 29 Aug 2012 11:46
Last modified: 16 Dec 2019 20:37

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