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Leukemias, the previously unknown role of 'nup98'
Like an actor who excels at both comedy and drama, proteins can also play multiple roles. Uncovering these varied talents can teach researchers more about the inner workings of cells. It also can yield new discoveries about evolution and how proteins have been conserved across species over hundreds of millions of years.
In a new finding, a team of investigators from the Salk Institute has uncovered in mouse cells a previously unknown job of a protein called nup98. In addition to helping control the movement of molecules in and out of the nucleus of the cell, they found that it also helps direct the development of blood cells, enabling immature blood stem cells to differentiate into many specialized mature cell types. Furthermore, they discovered the mechanism by which – when abnormally affected — this differentiation process can contribute to the formation of certain types of leukemia.
"This research was really a tour de force," says Martin Hetzer, Salk's Chief Science Officer and the study's senior author. "Tobias Franks, my postdoctoral researcher at the time and the paper's first author, used an approach that combined genomics, proteomics, and cell biology. This model wasn't easy to study, and he developed some very clever techniques in the lab to answer these questions." While Hetzer has no immediate plans to pursue their findings as an avenue for developing leukemia drugs, he says it's likely that others may pick up on this aspect of the research.
Disruption of cell differentiation that contributes to leukemia results from a single gene fusion — when two parts of chromosomes that are not meant to act on each other become linked. Says Martin Hetzer, cancers driven by a single genetic change like this have proven easier to block with drugs than cancer driven by multiple genetic alterations.
The findings are published in Genes & Development.
For years, Hetzer's lab has focused on a class of proteins called nucleoporins (nups for short), which are part of the nuclear pore complex. This complex regulates traffic between the nucleus (of the cell) where genetic material is located, and the cytoplasm where all other cellular structures exist. There are about 30 proteins in the nucleoporin family, and they carry out a number of different functions in addition to forming the nuclear pores in the nuclear envelope. Several of them are known to act as transcription factors, meaning they help regulate when and how genes are translated into proteins.
The finding that nup98 has this additional function was not entirely unexpected. Earlier research from Hetzer's lab had found that it plays a role in gene regulation in other cell types. But the team didn't know about its function in hematopoietic (blood) cells.
Until now the mechanism of how nup98 regulates transcription was not known. Investigators found that it acts through a link with a protein complex called Wdr82-Set1/COMPASS, which is part of the cell's epigenetic machinery. "This epigenetic process helps control when genes are transcribed into proteins and when transcription is blocked," says Hetzer, who also holds the Jesse and Caryl Phillips Foundation Chair.
Another thing that was different about this study is that it was done in mouse cells rather than simpler model organisms like yeast and fruit flies. "This is the first mechanistic insight of how one of these nup proteins works in mammals," Hetzer adds. "We have only touched the surface here in uncovering how this evolutionarily conserved mechanism works in mammalian cells." Future work in his lab will extend the study of nup98 to primates and humans.
Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML.
Authors: Tobias M. Franks, Asako McCloskey, Maxim Shokirev, Chris Benner, Annie Rathore and Martin W. Hetzer
This work was funded by the Razavi Newman Integrative Genomics and Bioinformatics Core Facility of the Salk Institute, the National Institutes of Health/National Cancer Institute, and the Helmsley Trust.
About the Salk Institute for Biological Studies:
Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.
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The localization of nup98 (green) in the nuclei (blue) of cancer cells.
Image credit: Salk Institute.