Chromatin Modification by Coactivators

The default state of many genes is thought to be one in which transcriptional activity is repressed by local chromatin structure, which acts to block access of trans-acting factors to the promoter. Core histones are thought to be central to the cohesion of this repressive state, and their abundance of positively charged lysine side chains have been suggested to interact with the negatively charged phosphate backbone of the DNA double helix. Acetylation of core histones is known to reduce their affinity for DNA by reducing their net positive charge and weakening their interaction with DNA. Since the identification of the yeast transcriptional adaptor GCN5 and its human homolog PCAF as proteins that catalyze the transfer of acetyl groups to histone lysine side chains (histone acetyl-transferases or HATs), it has become clear that many nuclear receptor coactivators possess this activity. The SRC family members SRC-1 and SRC-3/ACTR, the cointegrators p300 and CBP, the p300/CBP-associ-ated factor PCAF, and at least one member of the DRIP complex contains HAT activity. It seems, however, that acetylation by coactivators is not limited to histones: DNA binding by the transcription factors p53 and GATA-1 is stimulated after their acetylation by p300, and the DNA binding domain of the PR appears to be a target for acetylation by PCAF (M. Burcin, personal communication).

In addition to targeting HATs to DNA, evidence suggests that nuclear receptors also recruit protein complexes involved in the manipulation of chromatin domains to favor transcriptional activation. Members of the SWI/SNF complex, which couples ATP hydrolysis to noncovalent chromatin remodeling, historically have been associated with transactivation by nuclear receptors, and recent data have elucidated the molecular basis of this association. Mutations in SWI protein-encoding genes prevent transactivation in yeast of a GR-responsive reporter gene in the presence of cotransfected GR, whereas a wild-type yeast strain was able to support GR-dependent transactivation. Further, a human homolog of the SWI2/SNF2 proteins, BRG-1, interacts with ER in a ligand-dependent manner in a yeast two-hybrid assay, and the nucleoso-mal remodeling activity of the SWI/SNF complex is required for GR function in yeast. To substantiate this in a mammalian context, we have shown that GR regulation of a stably integrated MMTV promoter is dependent upon recruitment of complexes containing BRG-1 (see references in McKenna et al., 1999).

The nuclear receptor-interacting proteins TIF-1a and TIF-1P have been implicated by association in processes of chromatin remodeling. TIF-1a interacts with the heterochromatin-associated proteins mHP1a, MOD1 (HP1p), and MOD2 (HP1y) which in turn interact with mSNF2-P, a member of the SWI/ SNF chromatin-remodeling complex. A model has been suggested for TIF-1s in transcriptional regulation, in which formation of transcriptionally inactive heterochromatin by TIF-1s effects repression, and ligand-dependent association of TIF-1s with receptors mediates euchromatin formation (Le Douarin et al., 1998 and references therein) (see also Section 2.2.1.3.).

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