Gateway to Gene Control

Artist's illustration showing a portion of the genome. A long DNA molecule (red cord) is wrapped up into nucleosome structures with a histone-protein core (white spheres). The gateway to gene transcription spans the control switch (coils) on the left nucleosome to the beginning of the gene (green arrow) on the right nucleosome. Credit: Christina Ullman.

Penn State scientists reveal structure of gateways to gene control
The map pinpoints the locations of certain key gene-controlling nucleosomes -- spool-like structures that wrap short regions of DNA around a protein core. The research suggests how these nucleosomes, positioned at important transcription-promoter sites throughout the cell's DNA, control whether or not a gene's function can be turned on in a particular cell.

The study's many surprising findings together reveal an intimate relationship between the architecture of nucleosome structures and the underlying DNA sequences they regulate. "We now know exactly where these nucleosomes are positioned on the DNA molecule and which DNA building blocks they have wrapped up under their tight control," B. Franklin Pugh, professor of biochemistry and molecular biology at Penn State said. Among those building blocks, Pugh and his colleagues revealed the architecture of a critical gateway, controlled by the nucleosome, which must be unlocked before a gene can be transcribed.

The study revealed that almost all genes have the same kind of structure where transcription begins, that this beginning contains a critical gateway for transcription, and that the transcription gateway of each gene almost always is located at the same place on a nucleosome. The researchers also discovered some genes whose pattern is somewhat different from this norm, and these unusual sequences also are reported in the Nature paper. "We previously had a low-resolution idea that these structures all could be roughly in the same position, but now this high-resolution map makes it very clear that they really are in exactly the same position. It's a remarkably consistent arrangement," Pugh said.

The study also revealed that the nucleosomes at the transcription-promoter control centers occupy several overlapping positions on the DNA molecule, typically 10 base pairs apart, which exactly matches the periodic rotation of the DNA double helix." It is striking how well these positions match with the architecture of the DNA as it wraps around the nucleosome's protein core," Pugh said.

This result powerfully simplifies previous theories about the possible architecture of gene packaging. "There is a certain DNA sequence that shapes the gene's architecture in the same way, producing the same structure in every gene," Pugh said. The overall sequence of DNA building blocks is different in each gene, but the underlying architecture is the same."

Another discovery is that transcription-control centers tend to be located on the outside edge of the nucleosome and tend to face outward on the DNA helix, allowing the cell's transcription proteins to find them more easily. "This arrangement makes sense, because when signaling proteins arrive at a control center they are well situated to help push the nucleosome out of the way so the reading of the gene can begin," Pugh said.

"Previous research had indicated that DNA sequences located upstream of a gene might be a region that controls whether that gene is read or not, but we did not know the architecture of those sequences -- whether they were exposed and therefore ready for work. Now we know that the gateway to transcription is a part of this control region and that the nucleosome keeps it locked so the gene cannot be turned on until it is needed," Pugh said. When the gene is needed, the cell's molecular machinery loosens the DNA wrapping around the nucleosome, unlocking the transcription gateway to give access to the cell's molecular transcription machinery. "We think that the function of the nucleosome is to control the gateway to transcription," Pugh said.

The research reveals how the pieces of DNA that regulate genes at the transcription-promoter sites are packaged on nucleosomes. The knowledge that these sites are located on the outside edge of the nucleosome spool will help to focus research designed to manipulate gene expression. "Our study has provided a much clearer picture of the architecture of the DNA in the control regions, allowing us to understand much better how genes are regulated, which is important because gene regulation is a critical process for the survival of living things," Pugh explained.
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