English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Plus monthly

Global: Zendy Tools annual

Global: Zendy Tools monthly

Global: Zendy Free Plan

Background  Histone demethylases (HDMs) have a prominent role in epigenetic regulation and are emerging as potential therapeutic cancer targets. The search for small molecules able to inhibit HDMs  in vivo  is very active but at the present few compounds were found to be specific for defined classes of these enzymes.    Methodology/Principal Findings  In order to discover inhibitors specific for H3K4 histone demethylation we set up a screening system which tests the effects of candidate small molecule inhibitors on a  S.cerevisiae  strain which requires Jhd2 demethylase activity to efficiently grow in the presence of rapamycin. In order to validate the system we screened a library of 45 structurally different compounds designed as competitive inhibitors of α -ketoglutarate (α-KG) cofactor of the enzyme, and found that one of them inhibited Jhd2 activity  in vitro  and  in vivo . The same compound effectively inhibits human Jumonji AT-Rich Interactive Domain ( JARID) 1B  and  1D in vitro  and increases H3K4 tri-methylation in HeLa cell nuclear extracts (NEs). When added  in vivo  to HeLa cells, the compound leads to an increase of tri-methyl-H3K4 (H3K4me3) but does not affect H3K9 tri-methylation. We describe the cytostatic and toxic effects of the compound on HeLa cells at concentrations compatible with its inhibitory activity.    Conclusions/Significance  Our screening system is proved to be very useful in testing putative H3K4-specific HDM inhibitors for the capacity of acting  in vivo  without significantly altering the activity of other important 2-oxoglutarate oxygenases.

An High-Throughput In Vivo Screening System to Select H3K4-Specific Histone Demethylase Inhibitors