E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1.
2004
The fundamental unit of eukaryotic chromatin is the nucleosome, in which genomic DNA is tightly wrapped around a histone octamer comprising two copies of each core histone (H2A, H2B, H3, and H4) (25). Chromatin structure and gene transcription are regulated by covalent modifications in the N-terminal tails of histones, of which the best characterized is lysine acetylation (39, 42, 46). Generally, hyperacetylation correlates with transcriptional activation, while deacetylation is associated with repression. The enzymes that catalyze these transitions are histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. These enzymes are recruited to target genes by sequence-specific transcription factors, allowing both selective and diversified use of their coactivator and corepressor functions.
Transcription factors of the E2F family regulate cell cycle progression in higher eukaryotes (reviewed in references 7, 44, and 48). In mammals, six E2F species have been described: E2F1, -2, and -3 are believed to act primarily as transactivators and are thus commonly referred to as “activating” E2Fs, while E2F4 and -5 appear to be critical for repression of target genes. All of these proteins, however, possess a C-terminal transactivation domain (TAD) and thus have the potential to activate transcription. Through a subdomain within the TAD, E2Fs are bound by retinoblastoma (Rb) family proteins, or “pocket proteins”: E2F1, -2, and -3 interact with pRb, while E2F4 and -5 bind p107 and p130. These interactions are thought to counteract E2F-dependent gene activation by two mechanisms: (i) interference, i.e., preventing association of the TAD with basal transcription factors, and (ii) active repression, i.e., assembly of transcriptional repressor complexes. These include HDACs (2, 10, 28), histone methyltransferases (34), and the chromatin remodeling complex SWI/SNF (reviewed in reference 18). As a result, in quiescent cells, E2F target genes exhibit a repressed “heterochromatic” state, in which histones H3 and H4 are hypoacetylated and lysine 9 of histone H3 is methylated (11, 34, 38, 47).
In contrast to repression, the mechanisms of transactivation by E2F have not yet been elucidated in molecular detail. While E2F target genes are bound by E2F1 to -3 and exhibit hyperacetylated histones in the late-G1 and S phases (47), the causal relationship between these events remains unclear. In favor of a direct role of E2Fs in histone acetylation, they interact with HATs, including PCAF/GCN5 and p300/CBP. In reporter gene assays, these cofactors enhance E2F-dependent transcription, possibly through acetylation of E2F itself (1, 14, 26, 29, 30, 37, 49). E2F1 also binds TRRAP (26, 31), a subunit of the HAT complexes PCAF/GCN5 (51) and Tip60 (20). In spite of these observations, there is no direct proof that E2Fs act upstream, rather than downstream, of histone acetylation. Under certain circumstances, the simple removal of repressive E2F-HDAC complexes can induce downstream responses (19, 40, 56), suggesting that promotion of acetylation by E2F may not be required. Instead, like other transcription factors such as yeast SBF (4), E2F1 to -3 may bind chromatin only following histone acetylation and may activate transcription by recruiting basal factors. Consistent with this hypothesis, E2Fs have been shown to bind TBP, TFIIH (8, 17, 36, 50), and the Mediator subunit RING3 (6). Here, we show that chromatin association of activating E2F complexes is required to promote histone acetylation in late G1. We also provide evidence that five subunits of the Tip60 HAT complex (15, 20) are recruited to chromatin in an E2F-dependent manner.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
57
References
189
Citations
NaN
KQI