Deacetylation

Edited by: Eugene Russo J. Taunton, C.A. Hassig, S.L. Schreiber, "A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p," Science, 272:408-11, 1996. (Cited in more than 195 papers since publication) Comments by Stuart L. Schreiber, professor of chemistry at Harvard University Stuart Schreiber Vincent G. Allfrey, now a professor emeritus at Rockefeller University, first detected histone deacetylase, or HDAC, activity in nuclear extracts 34 years ago; soon after, he and other investigators showed a correlation between the acetylation state of chromatin and the rate of transcription.1 But the molecular characterization of the protein or proteins involved in deacetylation eluded identification, purification, and cloning until this paper's authors, from Harvard University, accidentally stumbled upon the sought-after enzymes in 1996. Adding to the novelty, when they checked the cloned gene's sequence against the gene bank database, they got a match with the yeast gene Rpd3p, a known transcriptional regulator. This HDAC, now referred to as HDAC1, would turn out to be the first of six human homologues that scientists have characterized. "It was not a case where we were aiming to solve this problem. It was a matter of surprise ..., but the minute you saw the surprise you thought, 'oh boy, this is really going to resonate with people,'" says senior author Stuart L. Schreiber. Schreiber adds that numerous other labs have subsequently used his team's results as a basis for their own projects. Schreiber's lab routinely uses a process directly analogous to a forward genetic screen to study the function of proteins. Just as developmental biologists might induce mutations in, say, zebrafish embryonic cells to deduce which genes are responsible for the development of which anatomical characteristics, Schreiber's lab uses small molecules (rather than mutant alleles) to study how certain chemicals affect cell morphology. In the case of their 1996 serendipitous discovery, they were interested in investigating the morphological effects of a chemical called trapoxin, known, based on previous studies, to trigger an alteration in cell morphology. After initially characterizing this morphological cellular change in some detail, lead author Jack Taunton concluded that the trapoxin was actually enhancing actin stress fibers. Schreiber and his colleagues thought, therefore, that by tracking down the protein that trapoxin was binding to, they'd find the molecular basis for an alteration in actin stress fibers. Instead they discovered that this previously uncharacterized protein was actually the HDAC responsible for the activity that Allfrey had first noted. Although the trapoxin did, as expected, affect the gene responsible for actin microfilament formation, as well as several other genes, much more intriguing were its effects on the HDAC enzymes farther upstream. "It was not as if we were part of the chromatin community or part of the transcription community," says Schreiber. "And it was not as if we were attempting to study chromatin or transcription. We had no idea that we were getting ourselves into that. But the discovery of the target of trapoxin then put us squarely into that field." Schreiber's lab continues to follow up on the discovery of HDACs by investigating exactly how they work. In an October 1998 paper, he and his colleagues reported the molecular characterization of the HDAC enzyme and showed that the enzyme is complexed with a nucleosome remodeling factor, an enzymatic function first discovered at around the same time as HDACs.2 That is, nucleosomes, the structures composed of histones, are themselves excellent substrates for histone deacetylase. The HDAC complex is one of several that remodel nucleosomes to some altered state that may be critical for allowing HATs and HDACs to gain access. According to Schreiber, this recent research brought together nucleosome remodeling factors and histone deacetylation, two new areas of gene regulation, by showing that they're actually interconnected or interdependent. It's one of the latest findings about enzymes and complexes whose interactions appear to be much more complicated and less clear-cut than initially thought. Scientists still don't know exactly how acetylation controls the rate of transcription, nor do they know how the functions of HATs and HDACs differ. The early assumption, that the two have equal but opposite effects, that HATs are activators and HDACs repressors, has been proven false, says Schreiber, based on genetic experiments as well as on genome-wide analyses from his lab and others. His lab continues to study the role of the six HDACs now identified, and to investigate their newly found nucleosome remodeling activity. Says Schreiber, "It's been really an amazing path that's taken us quite unexpectedly into several directions." V.G. Allfrey et al., "Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis," Proceedings of the National Academy of Sciences, 51:786-94, 1964. J.K. Tong et al., "Chromatin deacetylation by an ATP-dependent nucleosome remodeling complex," Nature, 395:917-21, Oct. 29, 1998.

Deacetylation

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