Among histones, histone H3 posttranslational modifications are probably the most studied. The first reports of histone H3 phosphorylation date back more than 30 years (113
). Since then, there have been extensive reports on the various modifications of histone H3, including phosphorylation of Ser10, Ser28, and Thr11. Even though studies indicate that these modifications in yeast do not have profound physiological effects, many recent findings with both mammalian and yeast systems point to the fact that the modifications have cellular consequences ( and ).
Fig. 3. (Top) Cartoon of the human H3 histone showing all the serine, threonine, tyrosine, and histidine residues. Residues that have been reported to be phosphorylated are shown with a red “P.” (Bottom) Schematic of some of the events occurring (more ...)
Phosphorylation of Ser10 on histone H3 (H3S10P) has been well characterized. H3S10P during mitosis is conserved in eukaryotes, and many studies have characterized this modification throughout the cell cycle (49
). In fact, H3S10P is used as a marker for mitotic cells. The kinases IpL1 and Snf-1 phosphorylate H3S10 in yeast (42
), whereas Aurora B, IKK, Rsk2, and AKT have been implicated in mammals (100
). The phosphorylation of H3S10 is first visible in the pericentromeric heterochromatin during late G2
phase. The modification subsequently spreads over the chromosomal arms, is completed by prophase, and remains visible during metaphase (52
). Immunofluorescence studies clearly demonstrate the temporal and spatial relationship between chromosome condensation and histone H3S10 phosphorylation (43
). Dephosphorylation at this residue starts during anaphase and is completed within telophase, even before traces of chromosome decondensation become detectable (52
). These observations suggest that H3S10 phosphorylation is important for chromosome condensation and segregation; however, there have been studies showing that H3S10 phosphorylation is necessary only to initiate the condensation of the chromosomes, not to maintain it (126
). Chromatin condensation/decondensation can be influenced by nucleosome remodeling. Interestingly, in their biochemical work, Shogren-Knaak et al. found that H3S10 phosphorylation does not directly affect SWI/SNF-dependent chromosome remodeling (114
). In that study, the researchers used nucleosomal arrays which had H3S10P-modified histone ligated to them and compared the accessibility of these arrays to the restriction enzyme SalI in the presence of the ATP-dependent yeast remodeling factor SWI/SNF with that of unmodified arrays. It was found that the H3S10P modification does not contribute to the remodeling event (114
). It is important to note here that in spite of evidence correlating H3S10 phosphorylation to chromosome condensation in mammalian cells, this phosphorylation does not have any appreciable physiological effect in yeast. It has been shown that in yeast, H3S10 phosphorylation peaks during mitosis, when chromosomes are maximally condensed and during the pachytene stage of meiosis (32
); however, the contribution of this histone modification to yeast cellular physiology has been questioned because mutation of serine 10 to alanine did not lead to any major defect. Budding yeast cells with S10A, S28A, and dual mutations (S10A S28A) were able to properly transmit mitotic or meiotic chromosomes during cell division (54
). The sporulation time and cell cycle timing were also identical to those of the isogenic types, indicating a mechanism by which the cells bypass the S10 phosphorylation requirement for proper chromosome segregation, in contrast to various other organisms which require this phosphorylation mark. In this regard, it has been suggested by Hsu et al. that residues in the amino terminus of histone H2B have a milieu similar to that of H3S10 and that phosphorylation at these sites might be able to compensate for the loss of H3S10 phosphorylation in budding yeast (54
). Hence, it seems that the need for H3S10 phosphorylation in chromosome condensation and segregation is not universal, which opens up an area for further investigations into other modifications which might act synergistically or redundantly in this process.
One open question in chromatin research is what the role of cell cycle-specific H3S10 phosphorylation might be; we wonder whether cell cycle-specific phosphorylation of the residue in conjunction with unique protein partners could participate in defined pathways, independent of the observed global spread of H3S10 phosphorylation over the chromatin. A recent study by the Allis laboratory reported that depletion or inhibition of Aurora B kinase, which phosphorylates H3 at Ser10, causes retention of heterochromatin protein 1 (HP1) on mitotic chromosomes; the authors suggested that H3S10P may mediate dissociation of HP1 from mitotic chromosomes, thereby facilitating their condensation and/or segregation (38
). It is interesting that trimethylation of a lysine residue (Lys9) of H3 is responsible for recruitment of HP1 to discrete chromatin sites, but during M phase, the release of HP1 occurs without changes in levels of H3 Lys9 trimethylation. This same study showed that phosphorylation of H3 Ser10 was responsible for the ejection of HP1 from the chromosomes during M phase. Thus, phosphorylation of Ser10 disrupts the interaction between the HP1 chromodomain and the trimethylated Lys9, thereby shifting the equilibrium to the HP1 unbound state. This work revealed the presence of a more complex regulatory mechanism within the cell that relies on the combinatorial readout of interaction between a more stable modification (H3 Lys9 trimethylation) and a more dynamic modification (H3 Ser10 phosphorylation) (38
). This histone modification-based switch may act as a part of a ‘histone readout,’ marking regions within the genome that need to be permanently silenced in the next generation. Use of such a binary switch to trigger HP1 ejection from mitotic chromatin may also be necessary for proper chromosome segregation.
In our laboratory, Loomis et al. took a biochemical approach to determine the possible interactions and functions of histone H3S10P (81
). Interestingly, the authors showed that H3 Lys9 trimethylated peptides could bind the splicing factor SRp20 in addition to HP1 protein. Moreover, HP1 and SR proteins (SRp20/ASF/SF2) failed to bind the chromatin in the presence of the phosphorylation mark. In vitro
studies further demonstrated that H3S10P is the major determinant that directs the loading and unloading of these proteins from the chromatin. These observations raised the question of whether release of HP1 and SRp20/ASF/SF2 from mitotic chromatin occurs independently or as a coupled phenomenon. Loomis et al. subsequently demonstrated that the dissociation of HP1 is dependent on the RNA-splicing proteins SRp20 and ASF/SF2, the binding of which is also H3S10 phosphorylation sensitive (81
). Additionally, they showed that SRp20 and ASF/SF2 bind to chromatin in a cyclic manner, remaining bound during interphase and in the postmitotic chromosome and then dissociating during mitosis. The dissociation of the proteins from mitotic chromosomes coincides with H3S10 phosphorylation. In other experiments, knocking down ASF/SF2 expression affected the dissociation of HP1 from the chromatin despite H3S10 phosphorylation, indicating a possible role of the SR protein in ejection of HP1 during mitosis. Previous studies on ASF/SF2 had indicated its involvement in cell cycle progression; these studies were confirmed by the observation that knockdown of AFS/SF2 inhibits G2
/M progression and delays G0
). Another interesting finding by Loomis et al. was that the phosphorylation of the SR proteins influences binding to H3S10P. Phosphorylated forms of both SRp20 and ASF/SF2 failed to bind H3S10P, and the association required dephosphorylation of H3S10 (81
). Thus, there appears to be an interplay of cellular kinase activity for histone marks (H3S10P) and proteins that recognize and are sensitive to these modifications for histone binding (SRp20, ASF/SF2), which introduces yet another layer of mechanistic cross talk between cellular and chromatin signaling pathways.
The cyclic patterns of binding, retention, and release of SRp20 and ASF/AF2 (and HP1) onto interphase, postmitotic, and mitotic chromosomes, as well as their roles in cell cycle progression, have been well documented, yet there is little evidence to indicate whether direct binding of ASF/SF2 and HP1 to the chromosome and its dissociation from mitotic chromatin are critical for chromosome condensation and cell cycle progression. This is primarily because of the limitations of the experimental system. Nonetheless, use of permanently chromosome-tethered recombinant ASF/SF2 containing chromo- or bromodomain fusions may facilitate an initial investigation of this important issue. Alternatively, use of H3S10A replacement histones (143
) in mammalian cell-based assays would help address, at least in part, the question of whether phosphorylation-sensitive binding and release of these proteins are indeed necessary for cell cycle progression. Other possibilities are that ASF/SF2 and SRp20 are necessary for splicing of key cell cycle regulatory mRNAs and that physical non-chromatin-mediated association of SR proteins with components of cell cycle regulators is important for their effect on cell cycle progression. With regard to a plausible role for SR protein release, we speculate that such an event might prevent premature binding of mitosis-specific proteins to chromatin and that release of SR proteins allows binding of yet-to-be-discovered proteins. A biochemical affinity purification scheme may help in the identification of such factors.
The Ser28 residue of the histone H3 N-terminal tail is also phosphorylated and known to play a role in mitosis. Like H3S10, H3S28 is also phosphorylated during mitosis and meiosis, albeit to a lesser extent (100
). The distribution of H3S28 phosphorylation is also very similar to that of H3S10P, initiating during prophase and then being maintained until early anaphase (43
). H3S28 phosphorylation has also been shown to coincide with chromosome condensation during mitosis (44
). The dynamics of H3 Ser28 phosphorylation is a consequence of the interplay between the kinase Aurora B and its phosphatase counterpart, PP1. PP1 is inactivated by Cdc2 kinase-mediated phosphorylation during mitosis, thereby allowing the appearance of the Ser28 phosphorylation mark on H3 (44
). After chromosome segregation, Aurora B no longer remains associated with chromatin, resulting in decrease in H3 Ser28 phosphorylation. The biological significance of H3S28 phosphorylation is not well understood, but there are data indicating that it may be involved in chromosome condensation and subsequent mitosis. It will be interesting to investigate whether phosphorylation of H3S28, similar to H3S10, assists in recruitment or ejection of certain factors from the chromatin in a cell cycle-specific manner to assist cell cycle progression. In this context, we note that overexpression of a kinase-dead mutant of Aurora B abolishes phosphorylation of both histones H3 Ser10 and Ser28, accompanied by incomplete chromosome condensation and misalignment of chromosomes on the metaphase plate (44
). These findings establish important roles for both H3 Ser10 and Ser28 phosphorylations as well as the kinases involved in chromosome dynamics. Taken together, these data highlight the importance of H3 Ser10 and Ser28 phosphorylation during mitosis. It will be necessary to determine whether Ser10 and Ser28 phosphorylation cross talk dictates, at least in part, chromatin dynamics during cell cycle progression.
A small fraction of nucleosomes also show phosphorylation of the Ser10 and Ser28 residues of histone H3 during interphase, and these modifications appear to be related to transcriptional activities (17
). The first link between gene expression induction and H3 phosphorylation was made in a study in which mammalian cells were treated with phorbol esters and growth factors and induction of immediate-early genes was accompanied by phosphorylation of H3 serine residues within the N-terminal tail (86
). Further investigation using chromatin immunoprecipitation (ChIP)-based assays confirmed these findings (18
). H3 Ser10 and H3 Ser28 phosphorylations have been observed in distinct chromosomal regions during interphase in cells treated with various transcriptional inducers. Cells treated with the phorbol ester 12-O
-tertadecanoylphorbol-13-acetate (TPA) show activated Ras/ERK/MAPK signaling, which in turn activates the mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2) (33
). These kinases then phosphorylate Ser10 and Ser28 on H3. The same study also demonstrated the requirement of H3 Ser10 phosphorylation to activate c-fos
in response to TPA treatment (117
). Other studies have shown that H3S10 phosphorylation-dependent c-fos
activation can be regulated by a variety of kinases depending on the nature of the stimulus: MSK1 and MSK2 phosphorylate H3S10 upon activation by ERK, as does tumor necrosis factor-α-induced IKK-α (4
). Additionally, PIM1 kinase has been shown to phosphorylate H3S10 in MYC-dependent transcriptional activation (142
). Other kinases, such as PKB/Akt and Rsk2, have also been reported to phosphorylate H3S10 (20
A recent work from the Cheung laboratory showed that direct phosphorylation of H3S28 on the c-fos
promoter by the kinase MSK1 is sufficient to activate transcription even in the absence of upstream signaling (76
). Moreover, H3S28 phosphorylation at the α-globin promoter by MSK1 could abolish the transcriptional repression imposed by the Polycomb complex. This modification also triggered a methyl-acetylation switch in the adjacent K27 residue, thereby transactivating the gene (76
). This indicates that histone modifications are the points of convergence of signaling pathways and that this nodal event is crucial for gene expression.
Another role of H3S10 phosphorylation during interphase involves transcriptional activation via the 14-3-3 family of proteins. Macdonald et al. have shown that certain isoforms of 14-3-3 bind phosphorylated H3 Ser10 or Ser28 (84
). It was subsequently shown that the binding affinity of 14-3-3 was stronger if the Lys14 residue was acetylated in addition to Ser10's being phosphorylated (127
). There is ample debate in this field as to whether transcriptional regulation by H3S10 phosphorylation is synergistic with or independent of adjacent lysine acetylation. The Berger laboratory showed in 2000 that H3S10 phosphorylation-mediated transcriptional activation of genes was functionally linked to acetylation of lysine 14 (80
). Their work showed that phosphorylation of H3S10 increased acetylation of the adjacent lysine residue by the histone acetyltransferase (HAT) Gcn5 at the promoters of genes that are transcriptionally activated. They further showed that promoters requiring HAT activity of Gcn5 almost always required H3S10 phosphorylation for their activation and that H3S10 phosphorylation improved lysine 14 acetylation at these promoters. A year later, the Berger laboratory further characterized the nutrient- and energy-sensing kinase Snf1 as the kinase responsible for transcription-associated H3S10 phosphorylation in yeast (79
). They studied the INO1 gene and concluded that Snf1-mediated phosphorylation of H3S10 resulted in Gcn5-mediated lysine 14 acetylation and subsequent transcriptional activation. Interestingly, however, Snf1 was not the kinase that promoted serine 10 phosphorylation, which preceded lysine 14 acetylation of the HO gene promoter during transcriptional activation, suggesting that additional yeast kinases exist and that these yet-to-be-identified kinases may be recruited in a gene- and signal-specific manner to promote HO gene transcription. Interestingly, however, more recent findings from the Berger laboratory have shown that the lysine 14 acetylation is not always preceded by serine 10 phosphorylation. At the promoter of the GAL1 gene, the Lys14 acetylation mark is present before the Ser10 phosphorylation mark; however, both the modifications are necessary for transcriptional activation of the gene (127
There is controversy regarding the role of H3S10P in coupling S10P to histone acetylation. The Peterson laboratory used purified GCN5-containing SAGA complex and nucleosomal substrate to show that there is no increase in the binding affinity of the SAGA complex for phosphorylated H3S10 (39
). Genome-wide binding studies under various physiological conditions should resolve this issue. Additionally, as with mitotic H3S10P, transcription-linked H3S10P may trigger release of repressor proteins such as the INHAT (inhibitor of acetyltransferase) complex (73
), thereby linking histone phosphorylation, inhibitor/repressor release, and hyperacetylation. In vivo
genome-wide binding studies will be necessary to test this possibility.
What additional mechanisms might be involved in H3S10P-mediated transcriptional activation? Work by Walter et al. revealed that the 14-3-3 family of proteins bind H3S10P-enriched promoters although they have higher affinity for the dual phosphorylation-acetylation mark, consistent with a synergistic cooperative model for histone modification cross talk in transcription even though the Lys14 acetyl mutant (K14R) showed only a 15% increased impairment in recruitment of the 14-3-3 protein Bmh1 to the promoter compared to the S10A strain (127
). Also, in mammalian cells, 14-3-3 ζ proteins were recruited to c-fos
promoters associated with dually modified H3 (phospho-Ser10-acetyl-Lys14 H3) (84
). 14-3-3 has also been reported to bind the phospho-Ser10 nucleosomes on the FOSL1 promoter to trigger transcriptional elongation through a series of downstream events involving H4K16 acetylation by enhanced recruitment of MOF histone acetyltransferase and subsequent recruitment of the bromodomain protein BRD4 (143
). In Drosophila
, H3 has been reported to be phosphorylated at Ser10 by the kinase Jil1, and as in mammalian cells, H3S10P-dependent recruitment of 14-3-3 proteins is necessary for early transcriptional elongation (63
). This is another insight into the role of H3S10 phosphorylation in transcription.
The cooccurrence of H3S10 and -28P in mitotic and interphase cells, albeit at different sites, raises the question of how cells distinguish these marks in a cell cycle-specific manner. We wonder if, similar to interphasic 14-3-3 proteins, there is a mitosis-specific protein that recognizes H3S10 phosphorylation. It would be interesting to identify such proteins and characterize the distinguishing features of such proteins transducing mitotic and interphase H3S10 phosphorylation events. Additionally, identification of Snf1 in yeast opens up the possibility of the existence of a similar mammalian kinase whose function might be to contribute to regulated transcription of specific promoters. In this context we note the Berger laboratory recently showed that the mammalian homolog of yeast Snf1, the signaling kinase AMPK, activated stress-induced genes by phosphorylating histone H2B serine 36 (13
). However, AMPK has not been shown to phosphorylate H3S10, and similarly, yeast Snf1 has yet to be shown to phosphorylate histone H2BS36, raising the possibility that the substrate specificity diverged for Snf1 kinase in yeast and mammals or that the mechanisms by which H3S10 and H2BS36 become phosphorylated and regulate transcription in yeast and mammals are different. In this context, we note that Zhang et al. observed EGF-induced phosphorylation of H3S10 at the promoters of Brf (transcription factor for RNA Pol III genes) and TBP genes. Also, H3 is phosphorylated at S28 by EGF directly on the promoters of tRNA, 5S rRNA, and 7SL RNA, thereby inducing transcription. Increased activation of these genes result heightened translation, leading to cellular transformation (136
). In any case, generation of knock-in mice with site-specific mutations (S10A, S28A, and S10A-S28A) will be extremely valuable in demonstrating the role, if any, of these residues in animal viability and key physiological pathways. As with yeast, such mutant mice might give us some surprising results.
Currently, another residue of H3, Thr11, is being actively studied, and a possible significance in transcription is emerging ( and ) (29
). The Thr11 residue of H3 is phosphorylated during mitosis and interphase by an array of kinases, including the serine/threonine protein kinase Chk1, protein kinase C-related kinase 1 (PRK1), and Dlk/Zip kinases (90
). Studies have shown that H3 Thr11 phosphorylation is predominant during mitosis and is concentrated at the centromeres. The Dlk/Zip kinase has been implicated in phosphorylating Thr11 of H3 preferentially at the centromeres, and Ser10 phosphorylation is replaced by Thr11 phosphorylation exclusively at the centromeres during mitosis (99
). This observation supports some novel role of Thr11 phosphorylation at the centromeres during mitosis. In two separate studies, H3 Thr11 was found to be phosphorylated differentially at the promoters of certain genes during interphase, resulting in different transcriptional outcomes. Metzger et al. showed that during interphase, PRK1 phosphorylates H3 at Thr11 on certain androgen receptor-responsive genes (e.g., PSA
) and facilitates gene activation by accelerating demethylation of the mono-, di-, and trimethylated Lys9 repression mark by the demethylase JMJD2C (90
). Furthermore, ligand-induced acetylation of H3 Lys9/Lys14 is facilitated following the demethylation event. Under such circumstances, the presence of serine 5-phosphorylated RNA Pol II can be detected at the target promoters, resulting in subsequent gene activation. It is interesting that phosphorylation of the adjacent Ser10 residue blocks demethylation of trimethylated H3 Lys9 by JMJD2A, which is a close homolog of JMJD2C (90
). These results indicate that the context and site specificity of the histone modifications are as important as the modification itself for such cross talk to occur. Interestingly, immunostaining of prostate cancer samples revealed increased levels of PRK1 and H3T11P, which correlated with high Gleason scores, indicating aggressive biology of the tumors. This finding suggests a role for PRK1 in prostate tumorigenesis, which probably occurs, in part, through transcriptional control of androgen receptor-responsive genes via H3 Thr11 phosphorylation (90
). PRK1 is known to regulate other nuclear receptors, such as mineralocorticoid and progesterone receptors; it will be interesting to investigate the broader role, if any, of this modification and the kinase in transcriptional regulation by other nuclear receptors and inducible transcription factors such as NF-κB. Similarly, PRK1 recruitment by AR may cause phosphorylation of nonhistone substrates, such as components of the enhanceosome or transcription initiation complex, and these additional events may also contribute to the transcriptional output of AR target genes. A possible link between PRK1-mediated H3 Thr11 phosphorylation and tumorigenesis in ER+/−
breast tumors would be a similarly compelling subject for investigation.
In other studies of H3 Thr11 phosphorylation, a structure-function analysis using phosphohistone peptides and S. cerevisiae
mutants showed that Thr11 phosphorylation is necessary for the recruitment of the acetyltransferase GCN5 and is required for optimal transcription from GCN5-dependent promoters (23
). It is interesting that GCN5 HAT activity is also required in H3S10-mediated transcriptional regulation of certain genes which need Lys14 acetylation for complete activation. We speculate here that a similar role for GCN5 might also exist in H3T11 phosphorylation-mediated gene activation. It will therefore be relevant to investigate the role of lysine 14 acetylation or acetylation of other adjacent lysines to see whether a broader histone modification cross talk exists. H3 Thr11 phosphorylation by Chk1 has also been related to the transcriptional repression of certain genes upon DNA damage (112
). DNA damage causes Chk1 to dissociate rapidly from the chromatin, resulting in a loss of H3 Thr11 phosphorylation. This in turn causes reduced binding of the acetyltransferase GCN5 at promoters of important cell cycle genes, like cyclin B1 and Cdk1, and subsequent reduced acetylation of H3 Lys9. Deacetylation of H3 at these promoters results in transcriptional repression (112
). It would be interesting to determine whether H3 Thr11 phosphorylation also acts as a recognition module for the docking of certain transcription factors or an unknown H3T11P-binding protein. It will also be important to resolve the question of the relative contributions of H3S10 and H3T11 phosphorylation in GCN5/SAGA recruitment and histone acetylation.
Recently, the Schule laboratory reported that threonine 6 of H3 is phosphorylated by protein kinase C beta 1 (PKCβ1
) in an androgen-dependent manner (89
). Here, an intricate cross talk between histone phosphorylation and methylation has been shown to exist to maintain the expression of certain genes in the presence of androgen hormone. The study revealed that androgen treatment results in colocalization of androgen receptor (AR), the lysine-specific histone demethylase LSD1, and PKCβ1
on target gene promoters. While LSD1 demethylates H3K4, resulting in gene repression, it was noted that in the presence of H3T6 phosphorylation, LSD1 could no longer demethylate residue K4, thereby allowing androgen-mediated gene expression. Moreover, it was observed that increased PKCβ1
levels correlated with more aggressive forms of prostate cancer and that knockdown of the kinase resulted in reduced cell proliferation. Together, these studies firmly established a role for threonine 6 phosphorylation in nuclear hormone action, cell proliferation, and cancer.
Recently, Shimada et al. reported that protein phosphatase 1γ (PP1γ) removes the phosphate group from H3 threonine 11 (111
). They showed that PP1γ was able to dephosphorylate phosphorylated H3T11 in a DNA damage-dependent manner (111
). This urges us to question the role of phosphorylation and dephosphorylation of H3T11 in DNA damage and opens up avenues for further work.
Thr3 of H3 has also been found to be phosphorylated. Wang et al. reported haspin to be the kinase responsible for the phosphorylation (128
). During mitosis, phosphorylation of Thr3 by haspin helps in the precise positioning of the chromosome passenger complex (CPC) at the inner centromeres. The authors showed that survivin, a protein component of the CPC, binds directly to phosphorylated Thr3 and ensures proper localization of the CPC. Studies with mutants of survivin revealed that the BIR domain of survivin is involved in the direct interaction with the H3 Thr3 phosphorylated residue. This study opened up the possibility that the BIR domain is a module for binding phosphorylated residues. It was also observed that H3 Thr3 phosphorylation prevents H3 from inhibiting Aurora B by interfering with its autophosphorylation. The authors concluded that H3 Thr3 phosphorylation might have a dual role: first, in positioning the CPC properly at the centromeres, and second, in facilitating activation of Aurora B by autophosphorylation at the inner centromeres (128
). Since H3 Thr3 and Ser10 have the same kinase, it would be interesting to investigate the existence of cross talk between the two modifications in various cellular contexts and signaling processes.
Finally, there are some lesser known C-terminal phosphorylations of H3 that appear to play roles in cellular physiology. H3 Thr45 is phosphorylated by protein kinase C, and this modification is involved in apoptosis of cells in which DNA is nicked (57
). Thr45 has also been reported to be phosphorylated in budding yeast by the kinase Cdc7-Dbf4. This modification has been related to proper replication of DNA in budding yeast (5
). Another significant C-terminal modification is H3 Tyr41 phosphorylation. A recent study has implicated this modification—driven by JAK2—in normal hematopoiesis as well as in leukemia (26
). Inhibition of JAK2 results in decreased H3 Tyr41 phosphorylation at the Imo2 promoter, resulting in reduced expression of this hematopoietic oncogene. Interestingly, similar to H3S10P, Tyr41 phosphorylation is also involved in the eviction of HP1 from chromatin. HP1α, but not HP1β, binds the Tyr41 residue of H3 through its chromodomain. Phosphorylation of H3Tyr41 excluded HP1α binding to this region. Consequently, inhibition of the nonreceptor tyrosine kinase JAK2 results in decreased expression of Imo2 along with reduced H3 Tyr41 phosphorylation and subsequent HP1α recruitment (26
). It remains to be seen whether H3 Tyr41 phosphorylation plays a role in a similar eviction of SR proteins from mitotic chromatin. While these results suggest that signal-specific modification of either Ser10 or Tyr41 might have identical physiological outcomes, it would be interesting to explore the possibility of novel signaling functions of H3Tyr41 through the recruitment of as-yet-undiscovered proteins.