Genetics

V.V. Ogryzko, R.L. Schiltz, V. Russanova, B.H. Howard, Y. Nakatani, "The transcriptional coactivators p300 and CBP are histone acetyltransferases," Cell , 87:953-9, 1996. (Cited in more than 143 publications to date) Comments by Vasily V. Ogryzko, Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development NEW TOOLS: NICHD investigators Vasily Ogryzko and Yoshihiro Nakatani used acetylation to begin to gain some insight into how chromatin is activated for transcription. It's the stuff of high school biology. Eukaryotic genomes are tightly packed into chromatin, which is made up of nucleosomes that are, in turn, composed of a complex of DNA and proteins (mostly proteins called histones). Until recently, however, researchers had little insight into how transcription factors are able to gain access to this highly condensed DNA to initiate the most fundamental of cell processes: transcription. Looking for answers, scientists hypothesized that perhaps acetylation of histones is important--that is, the addition of the radical CH3CO makes chromatin more open to transcription. Initially, researchers observed only a correlation, rather than a causal relationship, between histone acetylation and the activation of genes. But, by discovering that proteins known to be coactivators of transcription also had histone acetyltransferase activity (HAT), they were able to demonstrate that there is indeed a crucial causal relationship. A team from the University of Rochester identified the first protein to have both coactivator and HAT activity, yeast factor GCN5 (General Control of Nutrition 5) (J.E. Brownell et al., Cell, 84:843-51, 1996). Researchers at the National Institute of Child Health and Human Development (NICHD) followed up the Rochester team's findings with an investigation into the potential HAT activity of p300/CBP, another protein known to be a coactivator. They discovered that p300/CBP (actually two distinct homologous proteins) does have HAT activity and that it may contribute to transcriptional regulation through the targeted acetylation of chromatin. "It's even more powerful than [GCN5]," explains lead author Vasily V. Ogryzko, a visiting associate investigator at NICHD. "GCN5 can acetylate only free histones . . . [while] p300/CBP is able to acetylate all histones in the mononucleosomes." The acetylation of chromatin in the activation of transcription does not involve free histones, only histones packaged in the nucleosome. GCN5 is unable to get at these "buried" histones. "Two years ago, people were working on transcription, but nobody cared much about chromatin--only a few very hard-core aficionados," notes Ogryzko. "But now, people have the tools to change the state of chromatin and test their ideas of what role it plays in genetic processes." Subsequent research has shown that p300/CBP is also a coactivator of the well-known tumor suppressor p53 and that it is involved in p53-mediated apoptosis, or cell death (N.L. Lill et al., Nature, 387:823-7, 1997). According to Ogryzko, p300/CBP is involved in many such signal transduction pathways. In addition, p300/CBP has attracted attention as a result of recent research into histone deacetylases. Discovered at approximately the same time as acetylases, histone deacetylases like RPD3 and HDA1 perform a reaction opposite that of acetylases like GCN5 and p300/CBP; they have been shown to actually repress rather than activate transcription. Says Ogryzko, "It all came together. The whole field kind of exploded in a sense-- especially last year. A lot of people [have entered] the field now, and they're working on acetylases, deacetylases, and their roles in these different processes." Ogryzko and senior author and NICHD investigator Yoshihiro Nakatani have continued their work on acetylases, working with fellow NICHD investigators Alan Wolffe and Hui Ge. Last September, they published a paper that suggests that some components of RNA polymerase II transcriptional machinery are also acetylated (A. Imhof et al., Current Biology, 7:689-92, 1997). They also recently demonstrated that PCAF (p300/CBP associated factor) and p300, both HATs, come together to form a complex (X.J. Yang et al., Nature, 382:319-24, 1996). According to Ogryzko, the lab is now attempting to find out why there appears to be this redundancy of function.

Genetics

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NEW TOOLS: NICHD investigators Vasily Ogryzko and Yoshihiro Nakatani used acetylation to begin to gain some insight into how chromatin is activated for transcription.