Gerton Lab

Jennifer Gerton, Ph.D.

Investigator

Associate Professor, Department of Biochemistry & Molecular Biology
  The University of Kansas School of Medicine

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After graduate school Jennifer Gerton, Ph.D., radically expanded her research horizon—from analyzing the biochemistry of a single viral protein to monitoring how all 5700-plus genes of budding yeast make it through cell division.  


Cohesin refers to a protein complex (shown in red) that creates cohesion between two sister chromatids, which helps them to align and segregate properly at the metaphase to anaphase transition.

Image: Courtesy of Dr. Jennifer Gerton

Raised near San Francisco, Gerton was motivated in the mid-80’s to learn virology by the emergence of AIDS. “Living in the Bay area, everyone was aware of HIV and AIDS,” says Gerton. “My mom was a nurse who had treated AIDS patients before they knew it was caused by a virus.” (The HIV-1 retrovirus was identified in 1983 as the causative agent for AIDS).

Gerton entered Stanford University and earned a BA in human biology in 1990 and remained at Stanford for thesis work with Pat Brown. There she did biochemical studies of the HIV-1 integrase, which catalyzes integration of viral DNA into the host genome and was awarded a Ph.D. in microbiology and immunology in 1997.

But the advent of genomic technologies and Gerton’s desire to work in a “real live organism” pushed her to enter an entirely new field as a postdoc, namely, how chromosomes segregate, or separate, in an orderly fashion when cells divide.

The “real organism” Gerton chose as a model was the budding yeast Saccharomyces cerevisiae. “Proteins that ensure accurate chromosome segregation are evolutionarily conserved from yeast to man,” says Gerton. And the consequences of ending up with the wrong number of chromosomes after cell division is not just lethal to yeast: they are disastrous for humans and linked with cancer and genetic defects.

Gerton became particularly interested in a class of proteins called cohesins. “Cohesins are ring-like proteins that hold chromatin together once chromosomes are replicated and release them when cells divide,” says Gerton. Investigators had assumed that cohesin’s primary role was to orient bundled sister chromosomes correctly and help them properly separate.


A unique chromatin structure known as the centromere pins together replicated chromosomes before division. A plethora of proteins, including a specialized histone variant called Cse4, marks a spot where yet another boatload of proteins, the kinetochore, docks to connect replicated chromosomes to the mitotic spindle.

Image: Courtesy of Dr. Jennifer Gerton

But her work suggests they do more. For a 2004 PLoS Biology study she mapped all cohesin binding sites spaced along Saccharomyces chromosomes during cell division, the first genome-wide analysis of its kind.  Not only did cohesins favor AT-rich regions, but they preferred DNA between active transcription zones.

Concurrently, other labs were showing that cohesin mutations cause human disorders known as cohesinopathies, such as Cornelia de Lange syndrome, named for the doctor who discovered it. Children born with the syndrome show numerous growth deficits and impaired intellectual development.

“The genomic location of cohesins told us that these complexes have something to do with transcription,” says Gerton. “That was exciting news in terms of the human disease—it meant that cohesin mutations may alter not just cell division but gene expression.”

Later studies from her lab support that. A 2007 MCB paper showed that as transcripts elongate they may bump off cohesins bound to DNA. And in a 2009 JCB study the group mimicked human mutations in yeast and reported the very intriguing finding that mutant yeast grow normally but exhibit abnormal gene expression and chromosome positioning in the nucleus. Since then, her lab has acquired a mouse model of Cornelia de Lange syndrome and is extending their work to mouse and human cells.

Gerton is also interested in the unique chromatin structure known as the centromere, a region that pins together homologous replicated chromosomes before cell division. A plethora of proteins, including a specialized histone variant called Cse4, marks a spot where yet another boatload of proteins, the kinetochore, docks to connect replicated chromosomes to the mitotic spindle.

“We wanted to know how cells deposit this variant at the identical place every time the genome is replicated,” says Gerton. “Other factors must regulate the process.” In 2007, Gerton’s group, along with two other groups, identified Scm3. This factor turned out to be critical for the deposition of Cse4 at centromeres.


Molecular addresses of cohesion. Cohesin mutations cause human disorders known as cohesinopathies, such as Cornelia de Lange syndrome, named for the doctor who discovered it.

Image: Courtesy of Dr. Jennifer Gerton

Recently, her group identified a secondfactor involved in the regulation of Cse4. This factor, known as Psh1, is a ubiquitin ligase, an enzyme that modifies proteins to flag them for degradation. In a 2010 Molecular Cell paper they reported that Psh1 modifies and destabilizes Cse4, blocking its distribution to the “wrong” sites.

Gerton has been at Stowers since 2002 and in 2008 became an associate investigator. In recognition of her work’s significance to birth defects, Gerton received the March of Dimes Basil O’Connor Starter Scholar award in 2003.  

Before coming to Stowers, she completed two postdocs, one with Thomas Petes, then at University of North Carolina, where she began studying meiotic recombination in Saccharomyces, and a second with Joseph DeRisi at UCSF.

During that period Gerton occasionally collaborated with all three advisors, and in her first leap into the “new biology,” she teamed up with Petes, DeRisi and Brown to map recombination “hot spots”—sites of strand breaks that allow DNA exchange during meiosis—along all 16 Saccharomyces chromosomes. Published in 2000, that PNAS study, the first publication using microarrays to map protein binding sites, was proof that it is possible to predict where recombination will occur and set the stage for analyses in mammalian cells.

Ironically, although her thesis advisor Brown is credited with inventing microarray technology, Gerton did not begin concerted efforts at integrating those technologies into her own research until she was a postdoc.

“When I was a graduate student the whole lab was still working on retroviruses except for a couple of people on the periphery doing this crazy microarray work,” says Gerton, who has since taught courses in microarray use and construction at Cold Spring Harbor and the University of California, Santa Cruz. “Back then we just thought it was a quirky side project.”