After experimenting with a panel of chemical markers, Tsai and her colleagues published a study in Nature, in 2007, demonstrating that a group of small molecules called histone deacetylases (HDACs), which compact chromatin and render genes inaccessible for transcription, have the effect of restoring learning and long-term memories in their mouse model. “We found that if we give our mice these small molecules, this wonderful thing happens,” says Tsai. “We are able to completely restore their learning ability.” Now, Tsai and her colleagues have identified a particular HDAC that normally suppresses learning and memory. Thus, chemical inhibitors that selectively target this particular HDAC will likely have more potent and safer effects in clinical applications, they conclude in a study to be published in Nature. While much more work remains to be done to pin down the specificity of the molecules, Tsai believes that they may offer therapeutic promise for Alzheimer's.

HHMI investigator Yi Zhang, at the University of North Carolina at Chapel Hill, is also probing the impact of histone packing and modifications on fundamental biological processes and disease. “We are inquiring about what happens to the chromatin when a sperm enters an egg,” Zhang says. He wants to understand how germ cell fate is switched to somatic cell fate and how histone deposition and modification contribute to this process.

The Zhang lab is also exploring the role of histone modifications in obesity and leukemia. On February 4, 2009, Zhang and his colleagues published in Nature online a study on a knockout mouse that lacked a gene encoding a known histone demethylase, Jhdm2a. The mice were obese. Without the enzyme, they had lower metabolism and were less efficient at burning energy, yet their appetites were unaffected. This finding offers a new anti-obesity target that does not alter brain function, which most appetite-suppressing drugs do.

For her part, Luger is interested in Rett syndrome. When she learned that mutations in the MECP2 gene lead to this neurodevelopmental disorder (a discovery by HHMI investigator Huda Y. Zoghbi at Baylor College of Medicine) and that the MeCP2 protein is a methyl-binding protein that alters the structure of chromatin, she decided to investigate how interactions between MeCP2 and nucleosomes might offer clues about what causes the diseased state leading to Rett syndrome.

Given the complexity and dynamic nature of histones within the cell, Luger doesn't expect to unravel all their mysteries any time soon. One of the first priorities is to understand how histones orchestrate the multiple layers of DNA packaging, from the linear “beads on a string” to highly compacted chromatin. “We know at the first level how they organize, but we don't really know much else,” she says.

But today's structural methods are unlikely to crack the code, Luger says, because chromatin is constantly shape-shifting. Crystallography captures a snapshot of a billion static molecules, while nucleosome-nucleosome interactions are likely to be varied and “fluid” and therefore difficult to image. Luger says it will require a cadre of researchers, using a combination of techniques to elucidate the packaging of nucleosomes into chromatin. “I think a lot of people using very complicated approaches will have to put their heads together to pull this one off,” she says. “Which is really the fun part of science.”

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