HDAC complex to the promoter regions of the relevant subsets of genes, through interaction of the corepressors with transcription factors: Rb

Early embryogenesis in Xenopus proceeds from a fertilized egg to a blastula of approximately 4,000 cells in a series of 12 rapid cell divisions. Throughout this period there is no transcriptional activity (Prioleau et al., 1995; Hair et al., 1998), and the assembly of new chromatin from almost continuously replicating DNA is largely dependent on a maternal pool of histones and assembly factors. In general, chromatin assembly involves the association of pre-acetylated core histones with replicating DNA and subsequent stabilization of nucleosomes by histone deacetylation (Verreault et al., 1996). For instance, newly synthesized histone H4 is acetylated at defined lysine residues by a cytoplasmic histone acetyltransferase (HAT B; Sobel et al., 1994). Sequencing of the amino terminus of newly synthesized histone H4 from a range of different organisms has shown it to be diacetylated, at lysine residues 5 and 12 (Sobel et al., 1995), although yeast HAT B activity on histone H4 in vitro shows some variation from this pattern (Kleff et al., 1995; Parthun et al., 1996). Deacetylation would normally occur soon after histone deposition in new chromatin but information is only now becoming available as to how histones are accessed by histone deacetylase (HDAC) and how the deacetylation reaction is regulated. The aspect of histone deacetylation that has received most attention recently is its role in repression of the activity of specific sets of genes (reviewed by Grunstein, 1997; Wolffe, 1997). For instance, associations of HDAC1 (Taunton et al., 1996) with the retinoblastoma protein Rb (Brehm et al., 1998; Magnaghi-Jaulin et al., 1998), or with the corepressor of the mammalian Mad/Max complex, mSin3 (Alland et al., 1997; Hassig et al., 1997; Laherty et al., 1997), or with N-CoR, the corepressor of the thyroid hormone receptor (Alland et al., 1997; Heinzel et al., 1997), all serve to target the deacetylase complex to specific chromatin sites. These particular associations would appear to tether the HDAC complex to the promoter regions of the relevant subsets of genes, through interaction of the corepressors with transcription factors: Rb with E2F1 (Brehm et al., 1998; Luo et al., 1998); mSin3 with Mad-Max (Alland et al., 1997; Hassig et al., 1997; Laherty et al., 1997), and with the thyroid hormone receptor (Alland et al., 1997; Heinzel et al., 1997). Once tethered to the gene, the HDAC activity can target nearby nucleosomes, deacetylating core histones and contributing to transcriptional repression. Various multiprotein complexes containing histone deacetylases have been described, and some have been isolated and partially characterized. Complexes include yeast HDACA and HDAC-B (Carmen et al., 1996; Rundlett et al., 1996) and a range of complexes containing histone deacetylases 2441 Journal of Cell Science 112, 2441-2452 (1999)