ReviewHistone modifications in transcriptional regulation
Introduction
It is now difficult to recall that a scant five years ago many scientists working in the field of gene regulation believed chromatin was not a central player. Key observations that changed this view were that promoter-associated coactivators and corepressors possessed histone acetylation and deacetylation activity, respectively [1]. Since then, the amount of related research has been staggering, including investigations into identities of histone acetyltransferases (HATs), recognition of other histone modifications, and explorations of mechanisms (e.g. see 2., 3. for review). Moreover, understanding HAT/histone deacetylase (HDAC) function has become a useful paradigm for other modifications that are just now being discovered.
A unifying concept in this field is that of a histone code, which posits that the totality of modifications, both in kind and number, dictate a particular biological outcome 4., 5.. Strongly supporting the histone code hypothesis is evidence for several different covalent modifications, including acetylation, phosphorylation, methylation and ubiquitination (Fig. 1a), all involved in gene-specific regulation. In addition, documentation of patterns and order of modification events points to a code (Fig. 1b). These ideas culminate in the recognition of ‘off’ and ‘on’ states, characterized by alternative histone modifications. Although beyond the scope of this review, there is an emerging correlation with modifications, such as acetylation, of DNA-binding transcription factors themselves, which causes increased association with HATs for histone acetylation, indicating the existence of modification cascades 6., 7.. It is also important to point out that the transcriptional HATs also have an apparent non-transcriptional role in establishing the global genomic balance of acetylation 8., 9., 10., 11..
As the outcome of histone modifications has been examined, two non-exclusive models have emerged. One is that histone modifications affect chromatin structure directly. The second model is that modifications present a special surface for interaction with other proteins. Either model can be reconciled with the histone code hypothesis, both may operate simultaneously, and both have great explanatory power regarding the relationship between histone modification and gene control.
Section snippets
Histone acetylation
While the identities of histone methyltransferases (HMTs), HKs and HUs are still being worked out (see below), many HATs are now known. The most consistent functional characteristic of the HATs is that they are transcriptional coactivators (i.e. they do not bind directly to DNA but rather with DNA-binding activators). The fact that HATs are coactivators rather than DNA-binding moieties underscores the need for flexibility, regulation and alternative strategies in regulating chromatin and the
Histone phosphorylation
Histone phosphorylation involving Ser-10 of histone H3 has also emerged as an important modification, both in transcriptional activation and in chromosome condensation during mitosis [37]. As chromosome condensation and transcription are expected to involve opposing physical alterations of chromatin (i.e. closing of chromatin during mitosis and opening during transcription), the finding that the same modification is involved in both processes is circumstantial support for the
Histone methylation
There are two types of histone methylation, targeting either arginine or lysine residues. Histone arginine methylation is involved in gene activation and, again, methylases are recruited to promoters as coactivators. These are the CARM1/PRMT1 family of HMTs, and they predominantly target either H3 or H4, respectively 43., 44•..
The role of the SET domain family of lysine HMTs in heterochromatic gene silencing is very exciting. The hetero-chromatic Suvar3-9 enzyme in mammalian cells was the first
Histone ubiquitination
Two recent developments indicate that histone ubiquitylation is joining the ranks of important modifications. First, in S. cerevisiae, Lys-123 within the H2B carboxy-terminal tail is a substrate for the Rad6 ubiquitin ligase [53]. This modification is critical to mitotic and meiotic growth, although it is not yet clear whether it is involved in transcription. Second, TafII250 in the TBP-associated complex TFIID has been shown to possess histone H1 ubiquitylation activity [54], adding to its
Patterns, codes and models
Thus, specific modifications correlate with specific transcriptional states. In particular, histone H3 appears to be critical: known marks occur at Lys-4 (methylation), Lys-9 (methylation), Ser-10 (phosphorylation), Lys-14 (acetylation) and Arg-17 (methylation). In fact, around K9/S10/K14 in histone H3 there appear to be specific patterns for inactivity and activity (Fig. 1b). An inactive state is characterized by histone deacetylation at Lys-14, which precedes methylation at Lys-9. The enzymes
Conclusions
The initial finding that histone acetylation is a regulatory step involved in gene activation has now expanded in many ways. First, histone phosphorylation, methylation and ubiquitylation have each been correlated with gene activation or repression. Future revelations will identify new modifications of specific residues in the tails of histones H3 and H4, and will likely indicate modifications in both the amino and extended carboxy-terminal tails of H2A and H2B. Second, there is an
Acknowledgements
Thanks to Gordon Moore for critical reading of the manuscript. Grant support for research in the lab comes from The National Science Foundation (MCB78940) and The National Institutes of Health (GM55360 and CA78831).
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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