Scientists at the Salk Institute say they have discovered in mouse cells a previously unknown function for the Nup98 protein. Not only does it help control the movement of molecules in and out of the cell nucleus, Nup98 also helps enable immature blood stem cells differentiate into specialized mature cell types. The team also discovered the mechanism by which this differentiation process can contribute to the formation of certain types of leukemia. 

The study (“Nup98 Recruits the Wdr82–Set1A/COMPASS Complex to Promoters to Regulate H3K4 Trimethylation in Hematopoietic Progenitor Cells”) is published in Genes & Development.

“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,” write the investigators.

“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.”

“This research was really a tour de force,” says Martin Hetzer, Ph.D., Salk's chief science officer and the study's senior author. “Tobias Franks, Ph.D., 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.”

Dr. Hetzer's lab has focused on the Nup proteins, which regulate traffic between the nucleus of the cell and the cytoplasm. There are about 30 proteins in the nucleoporin family, and they carry out a number of different functions in addition to forming the nuclear pore. Several of them are known to act as transcription factors.

The finding that Nup98 has this additional function was not entirely unexpected, according to Dr. Hetzer. Earlier research from his 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 cells. 

In addition, until now the mechanism of how Nup98 regulates transcription was not known. The 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 to control when genes are transcribed into proteins and when transcription is blocked,” says Dr. 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 regarding how one of these Nup proteins works in mammals,” Dr. 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.

Although Dr. Hetzer says he has no immediate plans to pursue the team’s findings as an avenue for developing leukemia drugs, he believes it's likely that others may pick up on this aspect of the research. Disruption of the cell differentiation process 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. He says that cancers driven by a single genetic change like this have proven easier to block with drugs than cancer driven by multiple genetic alterations.

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