Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer

@article{Brown2006EndogenousMR,
  title={Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer},
  author={Brian D. Brown and Mary Anna Venneri and Anna Zingale and Lucia Sergi Sergi and Luigi Naldini},
  journal={Nature Medicine},
  year={2006},
  volume={12},
  pages={585-591}
}
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by repressing translation of target cellular transcripts. Increasing evidence indicates that miRNAs have distinct expression profiles and play crucial roles in numerous cellular processes, although the extent of miRNA regulation is not well known. By challenging mice with lentiviral vectors encoding target sequences of endogenous miRNAs, we show the efficiency of miRNAs in sharply segregating gene expression among… 

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References

SHOWING 1-10 OF 32 REFERENCES

MicroRNAs Modulate Hematopoietic Lineage Differentiation

The results indicate that microRNAs are components of the molecular circuitry that controls mouse hematopoiesis and suggest that other micro RNAs have similar regulatory roles during other facets of vertebrate development.

MicroRNA-responsive 'sensor' transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression

A technique for visualizing detailed miRNA expression patterns in mouse embryos is reported, elucidate the tissue-specific expression of several miRNAs during embryogenesis, and negatively regulates Hoxb8 and miR-196a, indicating that its restricted expression pattern probably reflects a role in the patterning function of the Hox complex.

Coordinate dual-gene transgenesis by lentiviral vectors carrying synthetic bidirectional promoters

Synthetic bidirectional promoters are developed that mediate coordinate transcription of two mRNAs in a ubiquitous or a tissue-specific manner that enabled efficient dual gene transfer in several tissues in vivo after direct delivery or transgenesis, and in a human gene therapy model.

Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes.

The results show that proximal pairs of miRNAs are generally coexpressed, and that in situ analyses of host gene expression can be used to probe the spatial and temporal localization of intronic mi RNAs.

Targeting lentiviral vector expression to hepatocytes limits transgene-specific immune response and establishes long-term expression of human antihemophilic factor IX in mice.

High levels of human factor IX, potentially in the therapeutic range, were reached and maintained long term in immunocompetent mice, without inducing antibody formation, prompting further studies in relevant animal models to explore the potential of in vivo LV administration for the gene therapy of hemophilias and other liver-based diseases.

Principles of MicroRNA–Target Recognition

The minimal requirements for functional miRNA–target duplexes in vivo are evaluated and classes of target sites with different functional properties are distinguished, indicating that miRNAs regulate a large fraction of protein-coding genes and that miRNA 3′ ends are key determinants of target specificity within miRNA families.

The Widespread Impact of Mammalian MicroRNAs on mRNA Repression and Evolution

It is found that these conserved targets are often highly expressed at developmental stages before miRNA expression and that their levels tend to fall as the miRNA that targets them begins to accumulate.