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Next-gen reappraisal of interactions within a cancer-associated protein complex
Date:1/15/2014

KANSAS CITY, MO- At a glance, DNA is a rather simple sequence of A, G, C, T bases, but once it is packaged by histone proteins into an amalgam called chromatin, a more complex picture emerges. Histones, which come in four subtypesH2A, H2B, H3, and H4can either coil DNA into inaccessible silent regions or untwist it to allow gene expression. To further complicate things, small chemical flags, such as methyl groups, affect whether histones silence or activate genes.

Among activator histones is a form of H3 decorated at a precise location (defined as H3K4) with three methyl groups (known as "H3K4me3"). Researchers knew previously that the presence of H2B exhibiting a single ubiquitin molecule stimulated the methylase that modifies H3K4, thereby increasing H3K4me3 levels. But how the methylase's activity was directed toward the appropriate targets had remained unclear.

Now, using biochemical, structural, and global sequencing techniques, researchers in the lab of Ali Shilatifard, Ph.D., an Investigator at the Stowers Institute for Medical Research, reveal an unanticipated mechanism underlying H3K4 trimethylation. Their study, published in the January 15, 2014 issue of Genes & Development, explains why H3K4me3 is deposited adjacent to a target gene promoter rather than haphazardly across the entire gene. This finding is significant because mutations in the human gene encoding the methylase responsible for H3K4me3 are associated with childhood leukemias, among other malignancies.

The work also illustrates the way powerful new genome-wide sequencing methodologies are impacting all molecular biology, including cancer research. "Here, we show that one cannot rely on methods that simply measure overall bulk H3K4me3 levels in vitro," says Shilatifard. "Only genome-wide sequencing could have revealed that H3K4 trimethylation was promoter-specific in non-mutant yeast."

This means that many assumptions about gene expression may
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Contact: Gina Kirchweger
gxk@stowers.org
816-806-1036
Stowers Institute for Medical Research
Source:Eurekalert  

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