Environmental Factor, December 2010, National Institute of Environmental Health Sciences
Adelman links chromatin architecture and gene regulation
By Negin Martin and Robin Arnette
According to NIEHS investigator Karen Adelman, Ph.D. (http://www.niehs.nih.gov/research/atniehs/labs/lmc/tre/index.cfm), one of the concepts that she and several other Institute researchers wanted to understand is how a cell differentially regulates two types of genes - those that only responded to specific environmental or developmental signals and the housekeeping genes that were on all of the time. Adelman's study (http://www.ncbi.nlm.nih.gov/pubmed/21074046) , published in the November issue of Cell, may have the answer, and it has to do with a gene's DNA sequence.
"If you tell me the sequence around a gene start site, we can now predict with some accuracy how that gene will be regulated and have some insights into what that gene's function might be," Adelman said.
Insight into gene regulation and its role in health and disease
Adelman's group found that many of the housekeeping genes contain a chromatin unfriendly sequence that leaves the promoter constantly open and available for expression whenever the RNA polymerase II (Pol II) arrives. In contrast, genes that shouldn't be continuously turned on - for example, those that regulate cell death - have a chromatin friendly sequence, which encourages the binding of chromatin or nucleosomes to the promoter, in lieu of the polymerase, and keeps the genes turned off. Importantly, many stimulus-responsive genes contain a paused Pol II on top of the genes' promoter site, preventing chromatin assembly and creating what Adelman calls a "musical chairs" scenario.
"When a paused Pol II is sitting on a promoter, it is poised to move into the gene and start transcription if the right cue comes from the environment, allowing for rapid gene induction," Adelman explained. "But if a polymerase isn't covering the promoter, then chromatin covers the gene, which could represses its transcription more permanently and reduce gene responsiveness to the appropriate signals."
A new way of thinking
Adelman's data indicated that if the cell needs to turn on a chromatin-covered gene, it can use chromatin remodelers to remove the chromatin and then use paused Pol II as a placeholder. At that point, gene activation involves triggering the release of paused Pol II, an event that can be both rapid, and finely tuned. This two-step regulation is ingrained in the DNA sequence, and the type of default chromatin structure that exists is different for genes with different fundamental functions.
Adelman said that although her group had shown that polymerase pausing is common and other researchers have examined the dependence of chromatin structure on DNA sequence, no one has previously linked these two phenomena.
"Genes that undergo pausing have their own distinct chromatin structure," she continued. "It is a new idea because it helps you understand why these genes are regulated so differently than other genes. The work really does open the door for taking a newly discovered gene and getting insight into its regulation by looking at the DNA sequence surrounding it."
Promising advances in immune research
Adelman performed her published studies on the fruit fly Drosophila, but she is now extending what she has learned into mammalian systems. Since she is interested in developmentally regulated and immune-responsive genes, she has established a system to study the inflammatory response in mouse macrophages.
Adelman's group and others have published data suggesting that the initial wave of the inflammatory response in mammals includes a number of genes with paused Pol II. In addition, others have shown that some of these genes can be activated independently of chromatin remodeling. Thus, Adelman wants to probe the connections between the genes that can be activated independent of chromatin remodeling and genes that possess a paused polymerase.
She said, "If we can show that there are classes of inflammatory genes that have a custom chromatin structure, for instance, a class independent of chromatin remodeling and a class dependent on chromatin remodeling, then drugs that target chromatin remodelers might be designed to be more selective based on knowing the types of gene regulation employed at pro- versus anti-inflammatory genes."
Citation: Gilchrist DA, Dos Santos G, Fargo DC, Xie B, Gao Y, Li L, Adelman K. (http://www.ncbi.nlm.nih.gov/pubmed/21074046) 2010. Pausing of RNA Polymerase II Disrupts DNA-Specified Nucleosome Organization to Enable Precise Gene Regulation. Cell 143(4):540-551.
(Negin Martin, Ph.D., is a biologist in the NIEHS Laboratory of Neurobiology Viral Vector Core.)