December 13, 2002

VUMC researchers connect signaling pathway to gene expression

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Susan Wente, Ph.D., professor and chair of Cell & Developmental Biology and a collaborator of one of the groups.

VUMC researchers connect signaling pathway to gene expression

Susan Wente, Ph.D. put her matchmaking skills to work last year, bringing together two scientific groups — one on each coast — that were working on a similar problem of how genes turn on and off.

“Both groups would have gotten to the same place, from completely different angles, but sharing information speeded the process,” said Wente, professor and chair of Cell & Developmental Biology and a collaborator of one of the groups. The teams recently published two papers in Science, showing that small molecules called inositol polyphosphates participate in chromatin remodeling — a process required for genes to be turned on and off.

“This is really basic fundamental biology,” Wente said. “Everyone wants to know how genes are regulated in terms of their expression patterns during development and during the changes that lead to disease.”

Understanding the control of gene expression is key to understanding cell behavior, Wente said. “When cells respond to the environment, when they are triggered to divide or to die, all of these things are thought to involve changes in gene expression.”

The current studies, together with work from Wente’s laboratory over the past few years, have found that a potential signaling pathway inside the cell regulates two aspects of gene expression: the synthesis of messenger RNA — the copy of DNA that is used to manufacture proteins — and its export from the nucleus. The signaling molecules, called inositol polyphosphates, were first linked to such nuclear processes three years ago by Wente’s group and collaborators at Duke University.

At that time, many types of inositol polyphosphates were known to exist inside the cell, Wente said, but their cellular roles were unknown. Wente didn’t go looking for a role for these molecules; she was simply pursuing interests related to how things move between the nucleus and the cytoplasm (the cell’s inner space). Using yeast, her laboratory performed a genetic screen to find genes and gene products linked to defects in the export from the nucleus of messenger RNA.

The genetic screen yielded several genes: two unknown genes, along with the well-characterized enzyme phospholipase C (PLC). PLC had been extensively studied by others, and its activity was known to be the rate-limiting step for the production of soluble inositol polyphosphates. But PLC function had not been linked to RNA export.

“We honestly banged our heads against the wall, because there were no reported connections between PLC, inositol signaling, and messenger RNA export,” Wente said. “This project basically stayed in the freezer for six months, and I kept asking people who worked on PLC how it might be connected to nuclear transport.”

When she teamed with John York at Duke, they quickly found that the two unknown genes were enzymes responsible for producing certain inositol polyphosphates. Their work not only linked the signaling pathway to messenger RNA export, but it also demonstrated that the pathway was involved in regulating messenger RNA synthesis by transcription (the copying of genes).

“It was really serendipitous, and a beautiful synergy of genetics and biochemistry,” Wente said. “We opened up an entirely new field that is studying how this signaling pathway regulates nuclear processes.”

The two new papers in Science have now connected the inositol polyphosphate pathway inside the cell to the nuclear process called chromatin remodeling. In the nucleus, DNA is associated with proteins and tightly packaged as “chromatin,” a structure that limits access to the DNA and the genes spelled out by it. Chromatin remodeling complexes — groups of proteins whose job it is to “unpack” sections of chromatin — provide access to genes so that they can be turned on or off. The current reports show that inositol polyphosphates modulate the activity of these chromatin remodeling complexes.

Aimee L. Miller, Ph.D., a postdoctoral fellow in Wente’s laboratory, participated in the studies with a group headed by Erin K. O’Shea at the University of California, San Francisco. The O’Shea group found a connection to the production of inositol polyphosphates using a genetic strategy to identify modulators of a particular gene’s transcription. In contrast, the companion Science article’s authors, a group led by Carl Wu at the National Cancer Institute, found that inositol polyphosphates could regulate chromatin remodeling in cell free assays (tests performed in a test tube).

Wente provided the common ground between the groups due to her role in discovering the pathway three years ago and open correspondence with both groups. Together, the two new papers present complementary genetic and biochemical evidence that inositol polyphosphates are involved in the recruitment and activity of chromatin remodeling complexes.

The research was supported by the National Institutes of Health and the Steven and Michelle Kirsch Foundation.