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March 2011

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Paper described as "tour de force" featured in microbiology journal

By Ernie Hood
March 2011

Ritu Rana, Ph.D.

Rana is a visiting fellow in the Human Metabolism Group, which is part of the NIEHS Laboratory of Toxicology and Pharmacology. (Photo courtesy of Steve McCaw)

Sailesh Surapureddi, Ph.D.

Surapureddi is a staff scientist with the group. (Photo courtesy of Steve McCaw)

Joyce Goldstein, Ph.D.

Goldstein is an ISI Highly Cited Author in Pharmacology, a member of the Faculty of 1000, and board certified by the American Board of Toxicology. (Photo courtesy of Steve McCaw)

WayneKid Kam, right

Intern WayneKid Kam, right, described early findings from the group's work on Med25 at the 2008 Summers of Discovery poster competition. (Photo courtesy of Steve McCaw)

A new paper from the NIEHS Human Metabolism Group (HMG) that describes for the first time a key transcriptional mechanism for regulation of drug and lipid metabolism in the human liver has been awarded "Spotlight" status by the journal Molecular and Cellular Biology, which is published by the American Society for Microbiology.

"Med25 is required for RNA polymerase II recruitment to specific promoters, thus regulating xenobiotic and lipid metabolism in human liver(" Exit NIEHS was published online in December 2010 and in the journal in February. HMG scientists Ritu Rana, Ph.D., and Sailesh Surapureddi, Ph.D., were co-lead authors, along with senior author and HMG Principal Investigator Joyce Goldstein, Ph.D., intern WayneKid Kam, and Stephen Ferguson of Invitrogen Corporation/CellzDirect. One reviewer called the paper "a tour de force [that] provides very convincing data...that will be of considerable interest to the transcription community."

Identifying a master switch for xenobiotic, drug, and chemical metabolism

The article reports the results of a series of experiments focusing on the novel role of the Med25 protein in regulating the expression of sets of genes in the cytochrome P450 family drug metabolism and those involved in fatty acid metabolism. Using microarray and imaging methods, mainly in primary human hepatocytes, which are a model for human liver, the researchers were able to demonstrate that "Med25 interacts with hepatocyte nuclear factor 4alpha (HNF4alpha) [a liver enriched receptor], and it up-regulates or regulates specific genes, including those involved in drug metabolism and lipid metabolism," Rana explained.

Med25 does so by changing the composition of the HNF4α-bound transcriptional complex from an inactive to an active state, recruiting RNA polymerase II to the specific sites to initiate transcription and the expression of the specific genes involved. That specificity is crucial. The liver controls a wide variety of metabolic processes, but "when Med25 levels are manipulated, the only metabolisms that seem to be affected are drug and lipid metabolisms," said Surapureddi. "Co-activators had been predicted to do that for a long time, and this is the first paper to show that."

"It's a master switch for certain genes," said Goldstein. "If Med25 was not there, you'd have a number of genes that wouldn't be responding to environmental chemicals, or clinical drugs you're taking with your morning coffee." Gene silencing techniques and up-regulation of the gene confirmed the necessity of Med25 to the process. "This was the first paper to show that if Med25 is not there, polymerase II cannot come, whatever other genes are there or not, it doesn't matter," said Surapureddi. "If Med25 is silenced and the other genes are normal, we cannot get polymerase II to the transcription complex."

When the team up-regulated or silenced Med25 and then ran microarray tests to identify which sets of genes were expressed, they discovered, said Rana, "Not all HNF4alpha-regulated genes were regulated by Med25. It's kind of a sub-categorizer - it's Med25 giving specificity to HNF4alpha to up-regulate a specific subset of genes."

Although there are no immediate clinical or translational implications of the research, the Med25 revelations are nonetheless significant discoveries to help elucidate cellular mechanisms involved in the all-important drug and lipid metabolic processes. And the impact of the protein may extend beyond just those mechanisms, according to Goldstein. "My guess is that this will have far-reaching implications to other genes, beyond those in just drug metabolism and lipid metabolism," she said.

Although Rana is leaving NIEHS shortly to assume another postdoctoral position at Yale University, the Med25 line of research in the HMG will continue, as the team seeks to characterize phosphorylation status involved with Med25 and HNF4alpha.

Citation: Rana R, Surapureddi S, Kam W, Ferguson S, Goldstein JA.( Exit NIEHS 2011. Med25 is required for RNA polymerase II recruitment to specific promoters, thus regulating xenobiotic and lipid metabolism in human liver. Mol Cell Biol 31(3):466-481.

(Ernie Hood is a contract writer for the NIEHS Office of Communications and Public Liaison.)

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