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The nucleosome, which is a fundamental repeating unit of chromatin, consists of about 200 base pairs of DNA and a histone octamer. Since the interactions between the histone proteins and DNA in the nucleosome hamper enzymes’ access to DNA, disassembly of nucleosomes is required for nuclear reactions such as transcription. Histone chaperones, which facilitate nucleosome assembly and disassembly, are therefore considered to play a critical role in transcription. Indeed, biological analyses have suggested that the histone chaperone CIA/ASF1, which is the most conserved histone chaperone in eukaryotes, is involved in histone eviction at the promoter regions in the transcriptional activation process. Other biochemical and biological studies have revealed that a critical signal of transcription activation is histone acetylation, which seems to function as a signal for the nucleosome disassembly in transcription. The acetylation signal is therefore likely to be transferred to histone chaperone CIA/ASF1. However, its molecular mechanism has remained elusive. In 2002, the Horikoshi group showed that CIA/ASF1 physically and genetically interacts with the double bromodomain (DBD) of CCG1 in the TFIID complex [1]. This result suggests that the interaction between CIA/ ASF1 and DBD plays a key role in connecting the histone acetylation and site-specific nucleosome disassembly. In order to elucidate this molecular mechanism at the atomic level, we determined the crystal structures of two molecular complexes containing CIA/ASF1. Initially, we determined the crystal structure of the CIA/ASF1–H3–H4 complex at 2.7 Å resolution [2]. This crystal structure showed that CIA/ASF1 interacts with the histone H3–H4 dimer and that the interaction inhibits nucleosome formation, suggesting that this complex occurs in the nucleosome disassembly process. In addition, the genetic analysis suggested that the interaction between CIA/ASF1 and histone H3 is involved in the transcription initiation process in yeast. Next, we determined the crystal structure of the CIA/ASF1–DBD complex at 3.3 Å resolution [3]. The genetic analysis, combined with structural information, showed that the interaction between CIA/ASF1 and DBD is also involved in the transcription initiation process in yeast. A ChIP analysis using a structurally designed DBD mutant suggested that CIA/ASF1 is recruited to promoter regions through the interaction with DBD and induces site-specific histone eviction around the promoter regions, leading to transcriptional activation. Our biochemical results showing that CIA/ASF1 can change its interacting partner from DBD to the histone H3-H4 dimer also supports this model. This is the first structure-based model of the biological signaling from histone modifications to structural change of the nucleosome (hi-MOST model) [3].

Crystal structures of histone chaperone CIA/ASF1-containing complexes