Cited by 108Genomics and Chromatin DynamicsRNA Interference and Gene DeliveryEpigenetics and DNA Methylation

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Closed Chromatin Architecture Is Induced by an RNA Duplex Targeting the HIV-1 Promoter Region

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Suzuki, Kazuo, Juelich, Torsten, Lim, Heidi, Ishida, Takaomi, Watanebe, Toshiki, Cooper, David A., Rao, Sudha, Kelleher, Anthony D.·2008·Journal of Biological Chemistry

DOI 10.1074/jbc.m709651200PMC PMC2516975

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Abstract

In some mammalian systems small interfering RNAs (siRNA) targeting homologous sequences in promoter regions of genes induce transcriptional gene silencing (TGS). We have previously reported the induction of TGS by an siRNA (prom-A siRNA) targeting the tandem NF-kappaB-binding motifs within the human immunodeficiency virus, type 1 (HIV-1), promoter region. Here we report that induction of TGS by prom-A siRNA is accompanied by immediate and sustained local recruitment of Argonaute-1 (Ago1), histone deacetylase-1 (HDAC1), and induction of dimethylation of histone 3 at lysine 9 (H3K9me2), processes known to be associated with transcriptional silencing. Elevated levels of H3K9me2 and HDAC1 spread upstream of the target sequence, and elevated H3K9me2 levels also spread downstream into the coding region. Moreover, this siRNA induces an immediate change in DNA accessibility to restriction enzyme digestion in the region of the transcription initiation site of the HIV-1. This change in accessibility is because of the relocation of a nucleosome known to be associated with this region of the integrated pro-virus. Although there is a theoretical possibility that the observed viral suppression could be mediated by the PTGS mechanism with this siRNA acting at the 3 (R)-long term repeat of the virus, we demonstrate that this siRNA, and three other U3 targeted siRNAs, are inefficient inducers of PTGS. These data strongly suggest that siRNA targeting the promoter region acts predominantly at a site within the 5 (R)-long term repeat of HIV to induce transcriptional silencing and alterations to chromatin structure of the HIV promoter region that extend well beyond the immediate siRNA target site. These induced changes are consistent with those described in latent HIV-1 infection.

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Authors: Suzuki, K., Juelich, T., Lim, H., Ishida, T., Watanebe, T., Cooper, D. A., Rao, S., & Kelleher, A. D.
Affiliations: St Vincent's Hospital Sydney (AU)
UNSW Sydney (AU)
The University of Tokyo (JP)
Corresponding author: Suzuki, Kazuo
ORCID: Suzuki, Kazuo
Rao, Sudha
Kelleher, Anthony D.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2008-08
Volume: 283
Issue: 34
Pages: 23353-23363
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m709651200
PMC: PMC2516975
OpenAlex: W1993695454
Cited by: 108
References: 79
Citations by year: 2026: 1 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 2 · 2021: 1 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 4 · 2016: 4 · 2015: 10 · 2014: 12 · 2013: 9 · 2012: 5
FWCI: 4.80
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 4445 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
ANU Open Research (Australian National University) (submittedVersion)
Funders: National Institutes of Health (pNL4-3)
Medical Research Council
National Health and Medical Research Council
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords: HIV-1 promoter, transcriptional silencing, siRNA, RNA duplex, AGO1, HDAC1, H3K9 dimethylation, chromatin structure, DNA accessibility, long terminal repeat, HIV latency
MeSH terms: Binding Sites, Chromatin, HeLa Cells, HIV, Humans, Models, Biological, Nucleosomes, Promoter Regions, Genetic, RNA, Transcription, Genetic, Transfection, HIV-1, NF-kappa B, Gene Silencing, RNA, Small Interfering

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Closed Chromatin Architecture Is Induced by an RNA Duplex Targeting the HIV-1 Promoter Region

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