Multifunctional protein contributes to blood cell development

December 21, 2017, Salk Institute

Like an actor who excels at both comedy and drama, proteins also can 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 a previously unknown job for 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 , enabling immature to differentiate into many specialized mature . Further, they discovered the mechanism by which—when perturbed—this differentiation process can contribute to the formation of certain types of leukemia. The findings are published in Genes & Development.

"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."

For years, Hetzer's lab has focused on a class of proteins called nucleoporins (nups for short), which are part of the complex. This complex regulates traffic between the nucleus of the cell, where the genetic material is located, and the cytoplasm, which contains other cellular structures. 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: This means they help to regulate when and how genes get 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.

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 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 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 ." Future work in his lab will extend the study of nup98 to primates and humans.

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 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.

Explore further: Scientists find interaction between two key proteins regulates development of neurons

More information: Tobias M. Franks et al. Nup98 recruits the Wdr82–Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells, Genes & Development (2017). DOI: 10.1101/gad.306753.117

Related Stories

Scientists find interaction between two key proteins regulates development of neurons

September 14, 2017
Salk Institute scientists have discovered that an interaction between two key proteins helps regulate and maintain the cells that produce neurons. The work, published in Cell Stem Cell on September 14, 2017, offers insight ...

Heart disease, leukemia linked to dysfunction in nucleus

November 2, 2016
We put things into a container to keep them organized and safe. In cells, the nucleus has a similar role: keeping DNA protected and intact within an enveloping membrane. But a new study by Salk Institute scientists, detailed ...

Gaining insight into the molecular mechanisms behind squamous cell cancer

December 19, 2017
Researchers at Kanazawa University report in EMBO Reports about a new molecular mechanism regulating cellular fate of squamous cell carcinomas. Squamous cell carcinoma (SCC) is a lethal cancer arising from the stratified ...

Protein turnover could be clue to living longer

August 30, 2017
It may seem paradoxical, but studying what goes wrong in rare diseases can provide useful insights into normal health. Researchers probing the premature aging disorder Hutchinson-Gilford progeria have uncovered an errant ...

Recommended for you

Unprecedented study identifies 44 genetic risk factors for major depression

April 26, 2018
A global research project has mapped out the genetic basis of major depression, identifying 44 genetic variants which are risk factors for depression, 30 of which are newly discovered. The study, by the Psychiatric Genomics ...

Key differences in young, older people's immune cells attributed to environment

April 26, 2018
Discoveries by Stanford University School of Medicine investigators may help explain why older people's immune systems often don't work so well, why different people's immune systems age at different rates, and why the environment ...

New testing provides better information for parents of children with form of epilepsy

April 26, 2018
Advances in genetic testing offer new insights to parents who have a child with a rare but serious form of epilepsy, epileptic encephalopathy (EE), found in one of about every 2,000 births and characterized by developmental ...

Natural barcodes enable better cell tracking

April 24, 2018
Each of us carries in our genomes about 10 million genetic variations called single nucleotide polymorphisms (SNPs), which represent a difference of just one letter in the genetic code. Every human's pattern of SNPs is unique ...

The role of 'extra' DNA in cancer evolution and therapy resistance

April 23, 2018
Glioblastoma (GBM) is the most common and aggressive form of brain cancer. Response to standard-of-care treatment is poor, with a two-year survival rate of only 15 percent. Research is beginning to provide a better understanding ...

Variants in non-coding DNA contribute to inherited autism risk

April 19, 2018
In recent years, researchers have firmly established that gene mutations appearing for the first time, called de novo mutations, contribute to approximately one-third of cases of autism spectrum disorder (ASD). In a new study, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.