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Home , Histone methylation

modifications: Now summoning sumoylation

Dafna Nathan, David E. Sterner, and Shelley L. Berger* Gene Expression and Regulation Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104

istones can be modified in Table 1. -related modifications of residues in histone proteins many ways to affect gene ex- Primary pression, including acetyla- ͞ Histone Modifying transcriptional Nature of tion deacetylation (1), phos- modification enzymes Demodifying enzymes effect modification phorylationH (2), (3), and ubiquitylation (4). Now, in this issue of Acetylation HATs HDACs Activation Dynamic PNAS, Shiio and Eisenman (5) report Methylation HMTs ??? Activation͞repression Static that sumoylation is yet another histone Ubiquitylation Rad6* Ubiquitin proteases (UBPs) Activation Dynamic modification, and, interestingly, it may Sumoylation UBC9* ULP-related proteases† Repression Dynamic regulate transcriptional repression. Al- *Although other enzymes are involved in sumoylation and ubiquitylation, UBC9 (yeast through human) though there may appear to be a bewil- is the only known E2 SUMO-conjugating enzyme, and yeast Rad6 is the ubiquitin E2 known to monou- dering array of histone modifications biquitylate in vivo. involved with gene regulation, there †Although histone desumoylation has not yet been characterized, studies with other sumoylated sub- could be a fairly simple paradigm under- strates demonstrate deconjugation by ULP proteases. lying them. Eukaryotic DNA is packaged within the nucleus through its association with his- can, depending on context, contribute a SUMO to its substrate, to the reporter. tone proteins (H2A, H2B, H3, and H4), ‘‘permanent’’ mark of either open, ac- Moreover, the targeted UBC9 results in forming the fundamental repeating unit of tive euchromatin or closed, repressed reduced levels of -associated , the . The precise (7). Perhaps, then, it is acetylated and marked ele- architecture of chromatin dictates whether not surprising that acetylation or meth- vation in heterochromatic protein 1 it is permissive or resistant to transcription ylation can occur on the same lysine (HP1). Notably, HP1 is a key structural and other DNA-templated processes, such residues to allow dynamic regulation by protein of heterochromatin and binds to as replication, DNA repair, and recombi- acetylation or more stable regulation by methylated Lys-9 on histone H3. HP1 nation. Hence, it is not surprising that methylation. can also contribute to repression of indi- mechanisms that promote changes in The current study by Shiio and Eisen- vidual euchromatic genes (14). chromatin structure are central to tran- man (5) on histone sumoylation and re- The amino-terminal tail of scriptional regulation. One key pathway to cent reports on histone ubiquitylation contains five , all of which may be alter chromatin structure involves covalent (4, 8–10) bring up many questions of how candidates for sumoylation. However, modifications of the histone tails. these much larger polypeptides function none of the histone proteins, including Small ubiquitin-related modifier within chromatin; i.e., are they activating histone H4, contain the putative consen- (SUMO) shares 18% identity with ubiq- or repressing, are they dynamic or static, sus sequence for sumoylation (␥-Lys-X- uitin and adopts a similar 3D structure do they occupy the same lysines, and, fi- Glu, where ␥ is a large hydrophic resi- (6). Ubiquitylation has a role in protein nally, do they oppose one another? Shiio due and X is any ). In degradation, whereas SUMO does not. and Eisenman provide some provocative addition, as described above, many of The size of SUMO and ubiquitin (11 observations and some initial answers these lysine residues may undergo other and 9 kDa, respectively) clearly distin- to these questions. modifications (Table 1). Consequently, it guishes them from the other known SUMO has been identified bound to is exceedingly difficult to study the phys- posttranslation modifications of histones, many proteins, but to understand his- iological significance of sumoylation. which are all small chemical groups. tone sumoylation, it may be most infor- One solution to this problem, used by SUMO and its ATP-dependent pathway mative to examine the known effects of Shiio and Eisenman as well as by others of conjugation to substrates are con- sumoylation on DNA-binding transcrip- studying sumoylation and ubiquitylation served in all eukaryotes investigated, tion factors. Sumoylation has been of nonhistone substrates, is to geneti- yeast through humans. shown to stimulate activity; notable ex- cally fuse SUMO to the putative target One important consideration regard- amples include heat shock factor HSF1 protein. Thus, Shiio and Eisenman ob- ing sumoylation of histones is that its and tumor suppressor p53 (11–13). serve that SUMO-H4 associates with target residue, lysine, is a putative sub- However, sumoylation most frequently chromatin and can be coimmunoprecipi- strate for multiple modifying enzymes correlates with decreased transcriptional tated with endogenous histone deacety- (Table 1). Acetylation of lysines is dy- activity (e.g., Elk1, Sp3, c-Myb, and c- lase 1 (HDAC1) and HP1. These data namically opposed by deacetylating en- Jun) (11) and, thus, repression of target provide strong, but indirect, evidence zymes. Typically, histone acetylation is genes. Interestingly, Shiio and Eisen- that sumoylation of H4 associates with activating and histone deacetylation is man’s study indicates that sumoylation agents mediating gene repression. Possi- repressing, and, in a symmetrical fash- of histone H4 also correlates with tran- bly analogous to this is a recent study ion, DNA-bound activators and repres- scriptional repression, at least within an proposing that p300͞CBP can repress sors recruit these enzymes to target artificial transfected reporter model. transcription by recruiting HDAC6 by genes (1). By contrast, lysine methyl- First, they establish that mammalian his- way of SUMO (15). ation on histones appears to be quite tone H4 is sumoylated both in vivo and stable (no have been re- in vitro, and this modification appears to ported despite considerable effort to be more efficient than sumolylation of See companion article on page 13225. identify them) and may, in fact, provide the other core histones. They show that *To whom correspondence should be addressed. E-mail: a ‘‘’’ mark (3). Consistent with expression of a reporter is decreased by [email protected]. its increased stability, lysine methylation targeting UBC9, which conjugates © 2003 by The National Academy of Sciences of the USA

13118–13120 ͉ PNAS ͉ November 11, 2003 ͉ vol. 100 ͉ no. 23 www.pnas.org͞cgi͞doi͞10.1073͞pnas.2436173100 Downloaded by guest on September 26, 2021 COMMENTARY

Fig. 1. Model for sumoylation function in transcription. Horizontal line represents a gene with a TATA box-containing promoter and ORF; ovals represent histone octamers͞nucleosomes. Through a , a DNA-bound activator can recruit a histone acetyltransferase (HAT) that acetylates histones and promotes chromatin structure amenable to transcription. This acetylation can potentially recruit SUMO-conjugating enzymes (E2͞E3) capable of modifying either histones or activators to give an attenuating effect. A and HDAC activity could then be recruited by a DNA-bound (possibly even with SUMO contributing to the interaction), deacetylating histones, and making way for the addition of repression-specific methylation marks, such as H3 K9-methyl, by an HMT. Finally, methylated histones (and possibly SUMO) would recruit HP1, contributing to chromatin structure in a static repressed state.

Based on Shiio and Eisenman’s obser- complex (16). Thus, it is possible that are now several examples of modifica- vations and the previous understanding sumoylation triggers direct association of tion patterns and sequences that relate of the role of histone modifications in both activities residing in a single com- to gene activation, some of which occur gene regulation, a model can be envis- plex. One easily testable question is on the same histone tail or on the same aged for the role of sumoylation in the whether histone H3 Lys-9 methylation amino acid (19). There is recent evi- context of the complex interplay of acti- occurs at the UBC9-repressed promoter dence that histone ubiquitylation is in- volved in gene activation (8, 9, 20). vating and repressing factors at the pro- before association of HP1. ͞ moter (Fig. 1). Gene activation corre- Thus, if ubiquitylation sumoylation of histones function to activate͞repress, lates with histone acetylation by histone respectively, it will be important to de- acetyltransferases, which are recruited Sumoylation may be termine whether they occur on the same within coactivator complexes to promot- lysine residues and whether they, in a ers by DNA-bound activators. Once the the signal that initiates simple reciprocal fashion, oppose one gene has been transcribed, then its activ- another’s activity. Such an antagonistic ity must be attenuated and then finally attenuation followed relationship occurs on both I␬B␣ (20) repressed. The signal for recruitment of and proliferating cell nuclear antigen sumoylating enzymes may be acetylation by gene repression. (PCNA) (21), where ubiquitin and itself, as suggested by the authors’ ob- SUMO modify the same lysine residue. servation that H4 sumoylation increases Despite the aforementioned challenges, with increasing H4 acetylation. The next Further research is required to deter- it would be informative to map the spe- step is HDAC-mediated removal of mine whether histone sumoylation is cific lysine residues in histones that are acetyl groups, recruited by DNA-bound relevant to repression of endogenous targeted by SUMO, to determine how . Repression then is caused by genes under physiological conditions. this modification may fit into the his- histone (HMT)-medi- Indeed, it is critical to demonstrate tone code. ated methylation, which is required for sumoylation of H4 at relevant genes and Thus, histone modifications are an binding of HP1, in turn providing the to examine by time course experiments expanding network, and lysine has emerged as a key residue for a number structural element for chromatin con- how sumoylation relates to RNA expres- of alternative modifications. Although densation. Thus, because Shiio and Eisen- sion. In terms of the mechanisms in- the ‘‘code’’ appears to be ever more man’s data place sumoylation as an volved, it is critical to understand the ͞ complex, eventually it may coalesce into event before HDAC HP1 recruitment, result of sumoylation and indeed, of a coherent pathway, once we fully un- sumoylation may actually be the signal ubiquitylation as well. Specifically, do derstand modification sequences, their that initiates a sequence of attenuation these large polypeptide modifications relative transience or permanence, and, followed by repression. cause direct structural changes in chro- most revealing, their physiological rele- One immediate question relevant to matin, or do they lead to the binding of vance. Histone H4 sumoylation has thus this model is whether histone sumoyla- effector proteins, similar to methyl-ly- emerged as a new potential repressive tion does indeed lead to methylation by sine associating with HP1? In the case mark, used in a transient manner as a way of deacetylation, as suggested by of H4 sumoylation presented herein, the possible counterbalance to activating interaction of SUMO-H4 with HDAC modification may directly recruit a com- marks. and HP1 and recruitment of HP1 to the plex possessing HDAC and HMT activity. UBC9-repressed reporter. Interestingly, Finally, a very attractive idea is that We thank G. Moore and M. Schwartz for critical reading of the manuscript. We ac- it was recently shown that both histone the various histone modifications that knowledge the National Science Foundation deacetylation and histone methylation occur during a biological process consti- and the National Institutes of Health for re- activities are present in one corepressor tute a ‘‘’’ (17, 18). There search support.

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