Simple fungus gives researchers new insight on key DNA process

April 23, 2012 By Eric Selker, University of Oregon
Flasks of the Neurospora crassa in Selker lab (Photo, Paula Grisafi)

( -- In the University of Oregon lab of Eric U. Selker, a simple fungus continues to provide big clues about a fundamental biological process that is essential for normal growth and development in plants and animals.

The easy-to-manipulate fungus studied in Selker's lab is Neurospora crassa, which serves as the simplest for a lot of basic molecular research. Not everything found in this readily translates to the biology of larger organisms, including humans, but discoveries can help point in new directions to consider, said Selker, a professor of biology and member of the UO Institute of Molecular Biology.

In 2001 in the journal Nature, researchers in Selker's lab determined that chromatin — a complex of nucleic acids and proteins, primarily histones, in the nucleus of cells — is important for normal methylation of . Since then, they have expanded their study of this vital process, which if not performed efficiently can misdirect proper signaling, leading to diseases such as cancer and disruptions to long-term memory.

In 2008, in Genes & Development, the lab documented a specific enzyme protein (phosphatase PP1) that is necessary for normal methylation, and two years later, in the same journal, reported a protein complex that prevents reckless spreading of methylation.

In a new paper, published online April 15 in the journal Nature Structural & Molecular Biology, Selker's team, led by postdoctoral researcher Shinji Honda, reported the discovery of a new protein complex called HCHC that controls the distribution of DNA methylation in yet a different way, specifically by removing acetyl groups from DNA that should be kept silent. They showed that HCHC works hand in hand with the DNA methylation machinery but, in certain chromosomal regions, is even more important than DNA methylation to maintain silence.

"This paper shows that there are at least two different silencing mechanisms working at heterochromatic regions," Selker said. "Shinji found that disruption of any of the four parts of this complex causes methylation to disappear from many regions of the genome but to become at heavier than normal elsewhere, namely at centromere regions. Paradoxically, loss of HCHC leads to activation of genes that are normally silent at these heavily methylated regions."

An accompanying commentary in the journal notes that Selker's findings appear to mirror shifts in DNA methylation that have been detected in human cancer cells. The rerouting of methylation noted in Selker's study seems to contribute to genomic instability.

"Genetic studies in such simple organisms are the cornerstone of basic research," said Kimberly Andrews Espy, vice president for research and innovation at the UO. "Initially, the discoveries may be far removed from any direct application to curing a disease, but such fundamental observations often are precursors to meaningful advances in the future."

Four co-authors on the paper with Honda and Selker were: Zachary A. Lewis, a former UO postdoctoral fellow who now an assistant professor at the University of Georgia; Kenji Shimada and Ragna Sack, both of the Friedrich Miescher Institute for Biomedical Research in Switzerland, where Selker started this work while on sabbatical with the director of the Institute, Susan Gasser; and Wolfgang Fischle of the Laboratory of Chromatin Biochemistry at the Max-Planck Institute for Biophysical Chemistry in Germany.

The National Institutes of Health supported the research through a grant (GM025690) to Selker.

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