Fred Hutch scientists report a finding in Drosophila fruit flies that may open new paths for understanding some of the genomic instability that leads to cancer in humans. The discovery could also offer novel ways to target diseases.
The study, led by the Basic Sciences Division’s Drs. Hector Rincon-Arano, Susan Parkhurst and Mark Groudine describes for the first time how a protein they named UpSET functions to affect gene regulation in Drosophila. Their findings were published in the Dec. 7 issue of Cell.
Red blood cell differentiation has been a long-standing interest of the Groudine Lab. In experiments designed to uncover genes that regulate this process, Rincon-Arano, a postdoctoral fellow Groudine’s lab, observed that a protein named Mixed Lineage Leukemia 5 (MLL5) played a key role in this process. Moreover, it had been known that the absence of this protein is associated with poor prognosis in certain human leukemias. Attempting to understand the function of the MLL5 protein in mammalian cells was complicated by the presence of another related protein. So Rincon-Arano turned to Drosophila, which has a single, conserved MLL5 gene, prompting collaboration with the Parkhurst Lab.
"Using Drosophila as a model allowed us to address the function of this machinery better than other systems because it only has one single gene," Rincon-Arano said.
In cells, DNA condenses itself by winding around proteins called histones, forming a complex known as chromatin. Chromatin controls how the DNA within the cell is used. A cell’s chromatin must open—through a process known as remodeling—in order for gene expression to take place.
UpSET, the MLL5-related Drosophila protein they identified, contains a SET domain, a protein motif usually found in proteins involved in gene activation. Surprisingly, however, the scientists found that UpSET recruits repressive proteins to active genes, and these repressors prevent the spread of open chromatin.
"That's contradictory, but the reason we believe it works that way is once you open or activate a region, you also have to modulate how much of the chromatin gets open," Rincon-Arano said.
Having boundaries for open chromatin is important to ensure that gene expression doesn't spread too far. "Otherwise, the whole genome becomes unstable through the inappropriate activation of usually silent neighboring genes and other DNA elements, and havoc ensues," Groudine said.
"People have been analyzing different classes of proteins that either activate or repress gene activity. This study uncovered a protein that recruits the gene repression machinery to active genes to fine-tune transcription, suggesting that the interactions are much more complex; it’s not going to be black and white," Parkhurst said.
Parkhurst said this discovery highlights how combining research using model organisms, such as the fruit fly, with that in mammals provides a powerful means of gaining insight into the mechanisms underlying human diseases.
Leukemia patients without the MLL5 gene have more aggressive disease, which could reflect UpSET’s unexpected role in genome instability. Now that the researchers better understand the protein’s activity, they plan to study the role of UpSET in myelodysplastic syndrome (MDS)—a pre-leukemia condition, Increased knowledge of UpSET function could provide a fertile testing ground for anti-cancer drugs that increase genetic stability.
Dr. Jeff Delrow, director of the Genomics shared resource, and Groudine Lab research technician Jessica Halow also contributed to the study. The National Institutes of Health funded the work.