Nature Biotechnology 24, 572 - 576 (2006)
Published online: 9 April 2006; | doi:10.1038/nbt1202
Preventing gene silencing with human replicatorsHaiqing Fu1, 3, Lixin Wang1, 3, Chii-Mei Lin1, Sumegha Singhania1, Eric E Bouhassira2
& Mirit I Aladjem11
Laboratory of Molecular Pharmacology, NCI, Bethesda, Maryland 20892, USA. 2
Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 10461, USA. 3
These authors contributed equally to this work.
Correspondence should be addressed to Mirit I Aladjem aladjemm@mail.nih.gov M94363M94363Transcriptional silencing, one of the major impediments to gene therapy in humans, is often accompanied by replication during late S-phase. We report that transcriptional silencing and late replication were prevented by DNA sequences that can initiate DNA replication (replicators). When replicators were included in silencing-prone transgenes, they did not undergo transcriptional silencing, replicated early and maintained histone acetylation patterns characteristic of euchromatin. A mutant replicator, which could not initiate replication, could not prevent gene silencing and replicated late when included in identical transgenes and inserted at identical locations. These observations suggest that replicators introduce epigenetic chromatin changes that facilitate initiation of DNA replication and affect gene silencing. Inclusion of functional replicators in gene therapy vectors may provide a tool for stabilizing gene expression patterns.
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