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The structure and function of a chromatin regulator in yeast has been determined using X-ray crystallography. Chromatin is a dynamic complex formed between DNA and proteins that packages up the genetic code in chromosomes. Its regulators are involved in countless cellular processes and can have a profound effect on human health and diseases making them important targets for the development of pharmaceutical therapies for a whole range of medical problems. The study could represent a major advance in understanding epigenetics, the influence of environmental effects on the expression of genes. "Epigenetics is a very important component for studying human health," Michael Kobor of the Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, and the Department of Medical Genetics, at the University of British Columbia, Vancouver, Canada, is on record as saying, "There is increasing evidence that epigenetic modifications are altered in a variety of diseases, such as cancer, and neurodegenerative disease." Kobor adds that, many different environmental factors affect the molecular machinery of the DNA packaging process. He and his colleagues are involved in collaborations looking at the relationships in fetal alcohol syndrome, asthma, and chronic obstructive pulmonary disease (COPD) as well as working with psychologists and population health scientists on the effects of socio-economic status on gene expression, for instance. Kobor and graduate students Alice Wang and Julia Schulze working with Emmanuel Skordalakes, Jennifer Gin, James Berger, and Jasper Rine of Department of Molecular and Cell Biology, at the California Institute of Quantitative Biosciences, at the University of California, Berkeley, have reported the structure and function of a key player in regulating chromatin in yeast (Saccharomyces cerevisiae) the protein Yaf9. This is a subunit of both the essential histone acetyltransferase complex NuA4 and the ATP-dependent chromatin remodelling complex SWR1-C, which deposits histone variant H2A.Z into euchromatin. The human "equivalent" of this protein is the close relative GAS41. The chromatin regulator Yaf9 contains a module called the YEATS domain, which is found in many other proteins implicated in chromatin regulation and cancer. Scientists have until now been unable to resolve the molecular structure and function of YEATS domain proteins. But Kobor and his colleagues have now used advanced X-ray crystallography to obtain the first detailed picture with atomic resolution (2.3 angstroms) of this important protein structure. Intriguingly, the team has found that the protein structure is conserved between yeast and humans, suggesting a deep shared evolutionary history. They also revealed a requirement of the YEATS domain for two different mechanisms by which chromatin can be modified. "The Yaf9 YEATS domain consisted of a beta-sandwich characteristic of the Ig fold and contained three distinct conserved structural features at least two of which are important for the protein's function. The structure of the Yaf9 YEATS domain was highly similar to that of the histone chaperone Asf1, a similarity that extended to an ability of Yaf9 to bind histones H3 and H4 in vitro," the team explains. They also used structure-function analysis, to show that the YEATS domain was required for Yaf9 function, histone variant H2A.Z chromatin deposition at speci?c promoters, and H2A.Z acetylation. Histones are the major protein constituent of chromatin and can be modified fundamentally by environmental effects.
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Kobor, getting to the heart of epigenetic chromatin regulation |
