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Latest CSHL Authors' Publications

CSHL Authors' Publications Database provides access to all articles published by Cold Spring Harbor Laboratory scientists (1892 - 2012).
We are in the process of creating a bio page for each CSHL Principal Investigator, including a link to their home pages, and a video clip of their current research.
Please contact the library for additions or comments.

Development of siRNA payloads to target KRAS-mutant cancer
Abstract: RNA interference (RNAi) is a powerful tool for target identification and can lead to novel therapies for pharmacologically intractable targets such as KRAS. RNAi therapy must combine potent siRNA payloads with reliable in vivo delivery for efficient target inhibition. We employed a functional Sensor assay to establish a library of potent siRNAs against RAS pathway genes and show they efficiently suppress their targets at low dose. This reduces off-target effects and enables combination gene knockdown. We administered Sensor siRNAs in vitro and in vivo and validated the delivery of KRAS siRNA alone and siRNA targeting the complete RAF effector node (A/B/C-RAF) as promising strategies to treat KRAS-mutant colorectal cancer. We further demonstrate that improved therapeutic efficacy is achieved by formulating siRNA payloads that combine both single-gene siRNA and node-targeted siRNAs (KRAS+PIK3C-A/B). The customizable nature of Sensor siRNA payloads offers a universal platform for combination target identification and development of RNAi therapeutics.
Yuan TL,
Fellmann C,
Lee CS,
Ritchie CD,
Thapar V,
Lee LC,
Hsu DJ,
Grace D,
Carver JO,
Zuber J,
Luo J,
McCormick F,
Lowe SW

Cancer Discov
  (0): Aug 6 2014

Transgenerationally inherited piRNAs trigger piRNA biogenesis by changing the chromatin of piRNA clusters and inducing precursor processing
Abstract: Small noncoding RNAs that associate with Piwi proteins, called piRNAs, serve as guides for repression of diverse transposable elements in germ cells of metazoa. In Drosophila, the genomic regions that give rise to piRNAs, the so-called piRNA clusters, are transcribed to generate long precursor molecules that are processed into mature piRNAs. How genomic regions that give rise to piRNA precursor transcripts are differentiated from the rest of the genome and how these transcripts are specifically channeled into the piRNA biogenesis pathway are not known. We found that transgenerationally inherited piRNAs provide the critical trigger for piRNA production from homologous genomic regions in the next generation by two different mechanisms. First, inherited piRNAs enhance processing of homologous transcripts into mature piRNAs by initiating the ping-pong cycle in the cytoplasm. Second, inherited piRNAs induce installment of the histone 3 Lys9 trimethylation (H3K9me3) mark on genomic piRNA cluster sequences. The heterochromatin protein 1 (HP1) homolog Rhino binds to the H3K9me3 mark through its chromodomain and is enriched over piRNA clusters. Rhino recruits the piRNA biogenesis factor Cutoff to piRNA clusters and is required for efficient transcription of piRNA precursors. We propose that transgenerationally inherited piRNAs act as an epigenetic memory for identification of substrates for piRNA biogenesis on two levels: by inducing a permissive chromatin environment for piRNA precursor synthesis and by enhancing processing of these precursors.
Le Thomas A,
Stuwe E,
Li S,
Du J,
Marinov G,
Rozhkov N,
Chen YC,
Luo Y,
Sachidanandam R,
Toth KF,
Patel D,
Aravin AA

Genes Development
  28 (15): 1667-80; Aug 1 2014
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