University At Buffalo Team Discovers How The Cell Nucleus Orchestrates Genetic Processes Nuclear Structure Coordinates "Grand Choreography In Space And Time"

BUFFALO, N.Y. -- In a perfect illustration of how structure determines function, researchers at the University at Buffalo have demonstrated how an exquisitely organized architecture in the cell nucleus controls precisely when and where genetic processes are activated, apparently influencing gene expression and regulation.

The work is reported in the current issue of Science (Sept. 4, 1998, Vol. 281, p. 1502-4).

Like a conductor waving a baton, the UB team reports, the intricate nuclear structure somehow orchestrates certain regions or "zones" in the nucleus to engage in, or refrain from, transcription or replication at designated times.

The research provides the best proof to date of how highly organized nuclear structures are, and how dramatically that organization affects the copying and writing of genetic information in an organism.

The results are particularly provocative, the researchers said, with work on the human genome so close to completion.

"There are so many great genetic probes available now that we will be able to test our findings on specific genes," said Ronald Berezney, Ph.D., principal investigator and professor and chair of the UB Department of Biological Sciences. "We will look at, say, a gene that codes for hemoglobin, and try to find out when and where it replicates and transcribes."

According to Berezney, such experiments could lead to an understanding of how different genes -- particularly those implicated in disease -- are related based on the proximity of their transcription and replication sites.

UB biologists working with researchers in the university's Department of Computer Science and Engineering used fluorescence laser-scanning confocal microscopy and three-dimensional image analysis.

Using green fluorescent tags to represent replication sites and red tags to indicate transcription sites, they have developed what they term "a dynamic mosaic model" of how such sites are distributed in the nucleus.

The clustering of green sites with green, red sites with red and only very rare cases of yellow, indicating overlap, demonstrates unequivocally that transcription and replication of DNA not only occur in two distinct areas within the cell nucleus, but that these sites occur as distinct clusters.

The results suggest that the whole genome is divided into subregions in the nuclear architecture and that different regions are activated in a progression.

"Huge amounts of genetic material are being turned on and off in a grand choreography both in space and time," said Berezney, "which opens up the idea that there may be a precise timing for when certain genes are expressed. That timing could turn out to be really important for the normal functioning of the cell," he said, adding that when, for some reason, the timing is not exactly right, it could be dangerous for the organism.

First author on the paper is Xiangyun Wei, a doctoral candidate in the UB Department of Biological Sciences. In addition to Berezney, the co-authors are Alan Siegel, a microscopy specialist in the department; Jagath Samarabandu, Ph.D., formerly a post-doctoral associate, and Professor Raj Acharya, Ph.D., and graduate student Rakendu S. Devdher, both of UB's Department of Computer Science and Engineering.

The work was funded by the National Institutes of Health.