In the Early Edition of PNAS this week, researchers identify 119 genes as potential drug targets — a finding they derived from a function-based gene identification using an shRNA library they constructed. The library contains about 150 shRNAs per gene investigated and was composed in an inducible lentiviral vector, enabling the propagation of growth-inhibiting shRNAS. Structure-activity analysis "yielded a set of structural criteria for shRNA efficacy, increasing the frequencies of active shRNAs up to five-fold relative to random sampling." They then used the library to decipher shRNAs that inhibit breast cancer cell growth by targeting potential oncogenes. "Short interfering RNAs against 19 of 22 tested genes in this group inhibited cell growth, validating the efficiency of this strategy for high-throughput target gene identification," the authors write.
In another paper published online this week, a pair of researchers at the Carnegie Institution in Baltimore report that "epigenetic stability increases extensively during Drosophila follicle stem cell differentiation." First, Andrew Skora and Allan Spradling observed random, heritable changes in GAL4/UAS transgene programming. They then used the frequency of this reprogramming to measure stage-specific epigenetic stability, and found that GAL4/UAS reprogramming declines more than 100-fold over the nine divisions encompassed in ovarian follicle stem cell differentiation. "Our results suggest that stem/early progenitor cells cannot accurately transmit nongenetic information to their progeny; full epigenetic competence is acquired only gradually during early differentiation," the team writes.
Researchers at the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute on Aging report they've detected more than 800 promoters wherein O-GlcNAc cycling occurs in Caenorhabditis elegans using anti-O-GlcNAc ChIP-on-chip whole-genome tiling arrays. Their whole-genome transcriptional profiling of O-GlcNAc cycling mutants "confirmed dramatic deregulation" of genes linked to insulin-like signaling, metabolism, aging, stress, and pathogen-response pathways. The authors suggest that their findings may have implications for studying human diseases of aging, such as neurodegeneration.
Investigators in the UK write that their examinations revealed no associations between polymorphisms of the gene coding for transforming growth factor β receptor type 1, TGFBR1, and colorectal cancer risk in an advance, online publication of PNAS this week. To determine whether rare variants were associated with CRC risk, the team sequenced the gene's exons in a sample of patients. They also assessed TGFBR1 allele-specific expression in CRC cases and controls. "No evidence of greater ASE in cases than controls was detected, and no haplotype around TGFBR1 could account for the ASE reported in other studies," the authors write.