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March 2011


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Chromatin meeting highlights genomic rearrangements and small molecule inhibitors

By Archana Dhasarathy
March 2011

Old North State Board Room at the North Carolina Biotechnology Center

The Old North State Board Room at the North Carolina Biotechnology Center offers an intimate setting for the monthly meetings of the ACCC. The program includes pizza and drinks for attendees at the evening lectures. (Photo courtesy of Steve McCaw)

Beth Sullivan, Ph.D.

Sullivan explored the consequences of defects in telomeres, which protect chromosome ends from degradation, and centromeres, which ensure equal segregation of chromosomes during cell division. (Photo courtesy of Steve McCaw)

Martin Herold, Ph.D.

Herold, above, listened to Sullivan's talk, as he waited his turn as the second speaker on the program. (Photo courtesy of Steve McCaw)

left to right, Sergei Nechaev, Ph.D., and Takashi Shimo, Ph.D.

Also in the audience were NIEHS Laboratory of Molecular Carcinogenesis postdoctoral fellows Sergei Nechaev, Ph.D., left, and Takashi Shimbo, Ph.D. (Photo courtesy of Steve McCaw)

NIEHS principal investigators and trainees attended the latest meeting of the Atlantic Coast Chromatin Club (ACCC) January 31. The ACCC is a special interest group that sponsors an ongoing series of talks by area scientists on the topic of chromatin, the complex of histone proteins and DNA that makes up our chromosomes, which is central to several important biological processes in the cell.

Held at the North Carolina Biotechnology Center, the meeting drew scientists from the NIEHS Laboratory of Molecular Carcinogenesis (LMC), Duke University, North Carolina State University, and the University of North Carolina at Chapel Hill (UNC-CH).

Genome rearrangements and structural abnormalities of chromosomes

Beth Sullivan, Ph.D.(http://www.genome.duke.edu/people/faculty/sullivan/) Exit NIEHS, an assistant professor in the Department of Molecular Genetics and Microbiology at Duke University, presented her research on genome rearrangements and chromosomal abnormalities. Chromosomes, the hereditary structures in our cells, are maintained stably by specialized structures such as telomeres and centromeres. Defects in these structures cause numerical and structural abnormalities of chromosomes, leading to reproductive failure, genetic diseases, and cancer.

One such genome rearrangement is called a dicentric, an abnormal chromosome containing two centromeres. Sullivan said that dicentrics in humans are surprisingly very highly stable, especially if one of the centromeres is inactivated. Her laboratory is trying to address how dicentrics are formed, what happens after they form, and how and when inactivation of one of the centromeres occurs.

To answer these questions, Sullivan and her colleagues developed a system to create these dicentrics in the laboratory. "We needed to have a human system that would be more relevant to what we see in patients," she said. To this end, they took advantage of a mutant dominant negative version of a protein called TRF2, which normally protects chromosome ends.

Using this elegant system, they noticed non-random dicentrics were formed by fusion of acrocentric chromosomes. Perhaps not coincidentally, acrocentric fusions are among the most prevalent naturally occurring chromosome abnormalities in humans. Expression of the mutant TRF2 also adversely affected nuclear organization of DNA and proteins, and the stability of the nucleolus, a structure in the cell nucleus that transcribes and assembles ribosomal RNA. Sullivan's laboratory is currently investigating the molecular basis for their observations, which have enormous significance for human health.

Selective small molecule inhibitors

Following Sullivan's talk, Martin Herold, Ph.D., a postdoctoral associate in the laboratory of Stephen Frye, Ph.D., at the UNC-CH Center for Integrative Chemical Biology and Drug Discovery(http://pharmacy.unc.edu/research/centers/center-for-integrative-chemical-biology-and-drug-discovery) Exit NIEHS, presented his research toward the development of potent and selective small molecule inhibitors targeting the malignant brain tumor (MBT) protein repeats. Access to the information encoded in chromatin by the cellular machinery is regulated via specific chemical modifications to DNA and histone proteins. Proteins in the cell control this process by "writing, reading, and erasing" this code. The MBT domains recognize methyl-lysine marks on histone tails, and their binding is involved in gene silencing, tumor suppression, and cellular differentiation.

Herold and his colleagues used a structure-based design to develop antagonists to the MBT repeat of a protein called L3MBTL1. Analyses of the crystal structure of L3MBTL1, and comparison to other domains, enabled them to identify features that were specific to the MBT repeat that could be used to improve potency and selectivity.

Using different kinds of assays, the researchers were able to pinpoint one of the compounds they screened, a nicotinamide compound called UNC669, which showed a 5-fold increased binding affinity and a 6-fold improved ligand efficiency compared to the canonical histone peptide alone. In collaboration with the Structural Genomics Consortium at the University of Toronto, UNC669 was the first small molecule to be co-crystallized with a methyl-lysine reader protein. Herold and his team are now using the compound in functional cell-based assays, to determine its effect on chromatin regulation in cells.

(Archana Dhasarathy, Ph.D., is a postdoctoral fellow in the Eukaryotic Transcriptional Regulation Group in the NIEHS Laboratory of Molecular Carcinogenesis.)

A regional special interest group on chromatin structure and function

The ACCC meets in the evening on the last Monday of the month at the North Carolina Biotechnology Center. The group is supported in part by NIEHS, the UNC-CH School of Medicine, the North Carolina Biotechnology Center, Duke Medicine, and companies such as current corporate sponsor Active Motif, a developer of innovative cell biology-based research tools and biocomputing resources.

In addition to its monthly meetings, each fall for the past five years, usually in October, the ACCC has also held an all-day annual conference at the William and Ida Friday Center in Chapel Hill, N.C., with high profile speakers.

NIEHS Transcriptional Responses to the Environment Group Principal Investigator Karen Adelman, Ph.D., and Eukaryotic Transcriptional Regulation Group Principal Investigator Paul Wade, Ph.D., were organizers of the 2010 annual conference, along with colleagues from Duke University and UNC-CH. The meeting attracted more than 100 scientists from North Carolina and beyond.

For information about upcoming meetings, please contact Professor Laura Rusche, Ph.D., at Duke University (lrusche@duke.edu).



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