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Fruit fly studies guide investigators to misregulated mechanism in human cancers
Date:11/19/2012

modification seems to be specific to enhancers, which are DNA elements that regulate gene expression in a tissue specific manner.

"After we discovered yeast COMPASS, we found that human cells have the same machinery," says Shilatifard. "But rather than one COMPASS methylase, human cells bear six. The question became, why are there six COMPASS family members in human cells?" However, it has not been clear which COMPASS family member functions as monomethylase on enhancers.

The first clue came from Shilatifard's 2011 Molecular and Cellular Biology study reporting that cells from the fruit fly Drosophila contained three COMPASS family members. In the new study, the group, led by postdoctoral fellow Hans-Martin Herz, Ph.D., unveiled the true fly "monomethylator" by blocking the expression of the components of each of the three candidates and imaging Drosophila tissues to assess methylation of H3K4. Attenuating the fly COMPASS-related complex called Trr (for Trithorax-related) caused genome-wide decreases in H3K4 monomethylation, while disabling the other two candidates did not.

To further the case, Herz collaborated with bioinformatician Alexander Garruss to examine where Trr "sits" genome-wide on fly genes and discovered that it associated with DNA regions called enhancer, the activation zones often flanking a target gene. Enhancers are required to switch genes on, a process Shilatifard likens to how an airline pilot commands his control panel by turning on and off switches to get the plane to move forward and gather enough speed to take off. "We found that Trr needs to move to an enhancer for it to become active," says Herz. "That suggests that Trr's presence orchestrates the transition from inactive to active enhancers."

Two mammalian COMPASS-like complexes structurally resemble Trr, which include proteins called MLL3 and MLL4. Focusing on MLL3, the group cultured mouse embryonic cells lacking
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Contact: Gina Kirchweger
gxk@stowers.org
816-806-1036
Stowers Institute for Medical Research
Source:Eurekalert  

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