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Linker histone binding and displacement: versatile mechanism for transcriptional regulation

JORDANKA ZLATANOVA^*1, PAOLA CAIAFA and KENSAL VAN HOLDE

^* Biochip Technology Center, Argonne National Laboratory, Argonne, Illinois 60439-4833, USA;
Department of Cellular Biotechnologies and Hematology, University of Rome ‘La Sapienza’, 00161, Rome, Italy; and Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331-7305, USA

¹Correspondence: Biochip Technology Center, Argonne National Laboratory, 9700 S. Cass Ave., Bldg. 202-A253, Argonne, IL 60439-4833, USA. E-mail: zlatanoj{at}everest.bim.anl.gov

	ABSTRACT

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 
In recent years, the connection between chromatin structure and its transcriptional activity has attracted considerable experimental effort. The post-translational modifications to both the core histones and the linker histones are finely tuned through interactions with transcriptional regulators and change chromatin structure in a way to allow transcription to occur. Here we review evidence for the involvement of linker histones in transcriptional regulation and suggest a scenario in which the reversible and controllable binding/displacement of proteins of this class to the nucleosome entry/exit point determine the accessibility of the nucleosomal DNA to the transcriptional machinery.—Zlatanova, J., Caiafa, P., van Holde, K. Linker histone binding and displacement: versatile mechanism for transcriptional regulation.

Key Words: DNA methylation • linker histone modifications • nucleosomal DNA • transcription regulation

	INTRODUCTION

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 
FOR MANY YEARS it has been clear that most (but not all) nucleosomes in eukaryotic chromatin are closely associated with histones of the lysine-rich class (H1, H1°, H5, etc.). These are often referred to as linker histones (LHs) because they are bound, at least in part, to the linker DNA between nucleosomes. It has long been believed that the primary function of LHs is to help create and/or maintain the compact higher order structure of the chromatin fiber. Indeed, there is abundant evidence that the highest compaction can be attained only when such proteins are present (for recent reviews, see refs 1 2 3 4 ). Because the compact fiber should be refractory to transcription, LHs have been thought of as nonspecific repressors. Repression might occur at either of two levels in transcription: initiation or elongation. Although compaction of chromatin structure could have global effects at either of these levels, it is difficult to imagine mechanisms by which compaction of chromatin fibers per se would selectively repress specific genes.

	LINKER HISTONES AS REGULATORS OF INDIVIDUAL GENE TRANSCRIPTION

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 
Several years ago it was suggested that LHs may play a more specific role in transcription regulation by acting at the level of critically placed individual nucleosomes rather than by general compaction of the fiber (5) . That LHs are actually involved in transcriptional regulation of individual genes was first unambiguously shown in two systems: the selective transcription of oocyte- and somatic-type 5S rRNA genes in early Xenopus development (e.g., refs 6 , 7 ), and the activation and repression of transcription of certain genes in Tetrahymena knockouts for histone H1 (8) . Recent in vitro experiments elucidated the mechanism of the differential expression of the two types of 5S rRNA genes in somatic cells and concluded that the differential effect of H1 on expression was due to the different manner in which H1 influences the positions of nucleosomes over the coding sequence of the oocyte and somatic genes (9 , 10 , reviewed in ref 11 ). Since in this case histone H1 is bound to both the transcriptionally active and inactive chromatin template, we will not include it in our ensuing discussion, which will focus mainly on transcriptional activation through H1 displacement.

Interesting results on the selective effect of LHs on transcription of individual genes were also obtained using an in vivo system for inducible overexpression of different histone H1 subtypes in cultured mouse cells (12 , 13) . Overexpression of H1^o, the differentiation-specific variant (14) , led to reduced steady-state transcription levels for all pol II genes studied; overexpression of another somatic H1 subtype, H1c, affected different genes differentially, showing either stimulation or no effect. Moreover, these subtype-specific effects were shown to be due to differences in the structure of the subtype globular domains (15) . In these cases, H1 clearly does not have the global effects on transcription that might be expected from its role in chromatin condensation. The molecular mechanism(s) underlying these subtype-specific effects on transcription of individual genes remain(s) to be elucidated.

To understand how specific regulation by LHs might occur, it is helpful to note that in many promoters or enhancers, the binding sites for critical transcription factors are buried in nucleosomal structure. Although some factors may be able to bind to DNA that is coiled onto nucleosomes, this does not appear to be the general rule (16) . It is possible that the nucleosome covering a binding site is actually removed to allow transcriptional initiation. There remain, however, many examples in which the impeding nucleosome seems to remain in place, but is somehow altered so as to allow access by transcription factors.

	LINKER HISTONES ARE GATES TO NUCLEOSOMAL DNA

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 
A reasonable mechanism for providing accessibility is the ‘unpeeling’ of a portion of the DNA from the histone core of the nucleosome (for a recent detailed treatise of the structure of the ‘core’ particle, see ref 17 ). This appears to be a spontaneous process on LH-depleted chromatin (18) or with isolated core particles (19) . However, the presence of LHs bound to nucleosomes occupying gene regulatory regions would be expected to act as a block against such unpeeling (Fig. 1 ).

View larger version (38K): [in this window] [in a new window]   Figure 1. Schematic depiction of the ‘gating’ scenario for linker histone-mediated transcriptional regulation. When LH is bound to the nucleosome, the ‘gate’ to nucleosomal DNA is closed and transcription factor binding is prohibited. LH removal is needed for opening factors to bind, thus making nucleosomal DNA accessible to further transcription factor binding and actual transcription. For examples of such opening factors, see Table 1 . LH may be alternatively replaced by a closing factor (Table 1) to lock the gate; such binding will lead to transcription repression since nucleosomal DNA is permanently inaccessible for transcription factor binding.

To understand how LH binding could exert such a blocking action, we must consider the way these histones interact with the nucleosomal structure. Most LHs possess a well-defined three-dimensional structure: a short amino-terminal random-coiled basic portion of the molecule is followed by a structured globular domain and a long carboxyl-terminal unstructured basic tail (see ref 1 ). The globular domain is believed to be situated at or near the entry-exit of the DNA into the particle, although there are at least three models for its exact location (reviewed in refs 4 , 20 21 22 23 ). The binding of the globular domain at this position allows the carboxyl-terminal tail to interact with both the incoming and outgoing linker DNA helices, bringing them close together, with the formation of a so-called ‘stem’ structure of 30 bp in length (24 , 25 , see schematic in Fig. 1 ). Thus, the LH binding site may be seen as a ‘gate’, which may either be closed when the protein is bound or opened when the protein is released, so as to allow invasion of the nucleosome by protein factors. In such a scenario, the problem of gaining access to a DNA site covered by a nucleosome reduces to the problem of removing a particular LH. Once a single protein factor has bound to a portion of the DNA partially peeled from a nucleosome, cooperative binding of other factors may be expected, as proposed by Polach and Widom (19 , 26) .

Alternatively, replacement of LH by other protein factors may repress transcription. A repressive protein factor would have to bind more strongly than LH to the nucleosome entry region to lock the DNA so tightly as to preclude nucleosome opening and hence transcription, even when appropriate transcription factors were present. It is our contention that LH replacements by both kinds of factors occur (see below) and constitute important, and subtly tunable, mechanisms for the regulation of transcriptional initiation.

	PROTEIN FACTORS THAT CAN DISPLACE LINKER HISTONES

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 
In the past several years, evidence has emerged that in certain cases LH molecules associated with nucleosomes in promoter regions can be directly displaced by transcription factors. Table 1 lists a number of especially clear examples, where both LH displacement and consequential regulation of transcription have been demonstrated. LH replacement by protein factors may result in both transcriptional activation (cases 1–3) and inactivation (case 4) (Table 1 ; Fig. 1 ).

Although it cannot be ruled out that displacement of LHs is an active process in which the incoming factor plays a direct role in the histone removal, scenarios that do not demand this are also tenable. It has long been known that LHs, in contrast to core histones, are labile enough to undergo some redistribution in chromatin under physiological conditions (27 , 28) . The temporary spontaneous release of LHs would allow recurrent ‘windows of opportunity’ for either ‘opening’ or ‘closing’ factors to bind (see Fig. 1 ). We define an opening factor as a transcription factor that by virtue of its binding to the LH binding site on the nucleosome would keep the gate to nucleosomal DNA open, i.e., would allow the unpeeling of the DNA end(s) off the histone octamer as required for gene-specific transcription factor binding. An opening factor may well be reversible in binding, allowing reformation of the closed nucleosome if transcription factors do not shortly enter to continue the unpeeling process. In the context of this transcription initiation scenario, closing factors should be defined as factors whose binding to the LH binding site is essentially irreversible, unless subsequent modifications in DNA and/or proteins promote their release. Once bound, they will preclude the dynamic unpeeling of the nucleosomal DNA end(s) necessary for transcription activation to occur.

A very simple example of a closing factor may be found in the LH variant H5, present in large amounts in terminally differentiated erythrocytes of birds and some fish. This histone has a much higher (200 fold; ref 29 ) affinity for DNA than do the H1 variants found in transcriptionally active cells, and it systematically replaces H1 during the final stages of erythroid differentiation. As it does so, transcription and replication activity essentially ceases. Other examples of bone fide closing factors could be the proteins that bind specifically to methylated DNA (30 , 31 ; see also below).

Finally, it may be relevant to note the existence of proteins that bind directly to H1 in vitro and thus may fall into a category distinct from either the opening or closing factors, which may not require direct interaction with the LH. A long known example is the nucleolar protein nucleolin (e.g., ref 32 ), which induces chromatin decondensation by binding to H1. A more recent example is prothymosin (ProT), an abundant acidic nuclear protein thought to be involved in cell proliferation. ProT shows high affinity for H1 in vitro (33) , and its complex with H1 can be immunoisolated from crude cell extracts (34) . Furthermore, a fraction of H1 is released when chromatin is challenged with ProT (34) . Chromatin from cells overexpressing ProT reveal biochemical characteristics of H1-depleted chromatin, again suggesting active removal of H1 by the protein (35) . These studies involving bulk chromatin should be extended to specific-gene chromatin to see whether the observed H1-mediated effect is a general consequence of H1 depletion on chromatin higher order structure or whether gene-specific effects could also be involved.

	Further levels of regulation will bias linker histone displacement

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 
It has recently become evident that LH repression or activation of transcriptional initiation is not only specific to different promoters and enhancers, but is also subject to fine-tuning via postsynthetic modifications of chromatin components. There are at least two ways in which such postsynthetic modifications may modify the interactions between LHs and chromatin. The first concerns phosphorylation and poly(ADP-ribosyl)ation of the LHs themselves, modifications that directly change the LH charge; the second one concerns DNA methylation and core histone acetylation/deacetylation, since these postsynthetic modifications have indirect repercussions on the affinity of H1 for DNA.

	Linker histone phosphorylation

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 
The significance of LH phosphorylation has long been the subject of debate; indeed, it has been at various times associated with both condensation and decondensation of chromatin (see refs 36 , 37 ). There are several sites for phosphorylation on each linker histone, and part of the confusion may result from the differential effects phosphorylation at different sites may have (see, for example, ref 38 ). Although there has also been evidence that phosphorylation is closely correlated with transcription, it has been unclear as to how this could function at the level of particular genes. A clue may be found in recent studies by Lee and Archer (39) , who demonstrate that only phosphorylated H1 can be displaced from the MMTV promoter by the action of glucocorticoid receptor. This observation, coupled with the discovery that long exposure to glucocorticoids leads to H1 dephosphorylation, explains the hitherto puzzling ‘refractory’ state of the promoter obtained on long exposure. Thus, there is now at least one clear example in which H1 phosphorylation is connected to the expression of a particular gene.

It may be relevant to note that phosphorylation/dephosphorylation of other, histone H1-like proteins may also be used as a tool for transcriptional regulation. There also appears to be at least one example in which dephosphorylation of an H1-like protein leads to gene activation. The protein MDBP-2-H1 is an H1-like protein that in roosters binds to the vitellogenin III gene promoter, inhibiting transcription (40) . Treatment with estradiol leads to dephosphorylation of this protein, similar to the observations with H1 in the MMTV system (see above). This in turn leads to release of the histone, accompanied by transcriptional activation.

	Linker histone poly(ADP-ribosyl)ation

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 
Poly(ADP-ribosyl)ation is a post-translational modification capable of regulating gene expression either by modulating chromatin structure or by directly influencing the expression of specific genes.

H1 histone is one of the best substrates (41) for poly(ADP-ribose) polymerase, which builds or transfers ADP-ribose polymers onto H1 and other proteins both in a covalent and/or noncovalent manner. Covalent binding leads to the presence of short ADP-ribose chains on the modified protein, e.g., 8–10 units of ADPR on H1 (42) , whereas noncovalent binding leads to attachment of long and branched polymers (100–200 ADPR units) to specific domains on the protein (43) . Noncovalent interactions are far stronger than would be expected from simple electrostatic interactions, so much so that this binding is resistant to strong acids, detergents, chaotropes, and high ionic-strength conditions (43) . Poly(ADP-ribose) polymerase is involved in the noncovalent modification through an unusual mechanism: to perform this transfer step, termed heteromodification, it is necessary for the two monomers in the catalytically active dimer to first modify each other, building long and branched polymers on numerous sites in their automodification domains (44) . It is clear that the presence of ADP-ribose polymers on the linker histone molecule changes its charge dramatically and is expected to affect both H1-DNA and H1-H1 interactions, which are important in chromatin organization. Electron micrographs have shown that in vitro poly(ADP-ribosyl)ation of polynucleosomes leads to significant relaxation of chromatin structure (45) . Poly(ADP-ribosyl)ation does not detach H1 from the internucleosomal regions, an observation subsequently confirmed by a different experimental approach (42) .

If poly(ADP-ribosyl)ation does not cause or help LH displacement, what is the possible mechanism whereby this modification modulates the expression of specific genes? Recent evidence suggests that in vivo this modification plays a regulatory role in protecting genomic DNA methylation pattern (46 , 47) , particularly in maintaining the unmethylated state of CpG islands in the promoters of constitutively expressed housekeeping genes (48) (see also below). The molecular mechanism involved in the interplay between H1 poly(ADP-ribosyl)ation and gene-specific methylation pattern is still enigmatic, but in vitro experiments suggest that the poly(ADP-ribosyl)ated form of a specific genic variant of H1, H1e, is present in decondensed chromatin structure where the housekeeping genes are located and inhibits the methylation of their CpG islands (46) .

	Core histone acetylation

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 
It has long been known that there is a strong correlation between gene expression and acetylation of certain amino acid residues, particularly at specific sites in the tails of histones H3 and H4 (36 , 49) . Interest in this modification has intensified with recent discoveries of acetylase and deacetylase functions associated with the transcriptional machinery (50 , 51) . The possible significance of core histone tail acetylation has generally been attributed to the role of these histone tails in maintaining higher order structure. Indeed, the recent suggestion from the crystal structure of the core particle (52) that the H4 tail of one core particle contacts an H2B molecule in an adjacent core particle has sparkled renewed interest in this view, even though there is no obvious connection between core particle crystal structure and chromatin fiber structure.

The effect of core histone acetylation could be, at least in part, on the interaction of core histone tails with LHs. Indeed, earlier observations that highly acetylated chromatin fractions are significantly depleted in LH (53) and that histone acetylation alters the capacity of H1 to condense transcriptionally active chromatin (54) may reflect such an effect. In this context, the results of a paper by Juan et al. (55) are of especial interest. These authors studied the H1-mediated inhibition of upstream factor binding to reconstituted chromatosomes, and found that inhibition of factor binding was essentially lost when the core histone tails were removed and considerably alleviated by their acetylation. More recent experiments have confirmed that although the tails of the core histones do not affect the location of the LH in the chromatosome, they do affect its binding affinity (56) . Thus, these experiments suggest that at least one way in which core histone acetylation promotes transcription is by facilitating the release of specific LHs adjacent to the modified nucleosome.

Although the results described above are clear, there remains an observation in apparent contradiction to the idea that core histone acetylation can facilitate the release of LH. Ura et al. (57) found that reconstitution of histone H5 on mononucleosomes was insensitive to core histone acetylation. At least two arguments may be addressed toward this observation. First, the binding studies were not quantitative; there could well be differences in affinity that would go undetected [note that Juan et al. (55) and An et al. (56) observe quantitative, not qualitative, effects]. Second, the use of H5 rather than H1 in these experiments seems especially inappropriate to questions involving potential mechanisms of transcriptional activation. Perhaps H5 is simply insensitive to such effects, consistent with its role as a permanent repressor of transcription (see above). Clearly, further studies are needed to clarify the way core histone acetylation works in transcriptional regulation as well as the functional interconnection, if any, between LH binding and such acetylation.

	DNA methylation

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 
It is widely accepted that DNA methylation plays a direct role in regulating the expression of some specific genes (58 , 59) . In particular, the ‘CpG islands’ (so named due to their high content of CpG dinucleotides) in the promoter regions of constitutively expressed housekeeping are unmethylated, this condition being essential for the expression of the associated gene (60) . Note that CpG islands have been found recently in several tissue-specific and imprinted genes, within the genes themselves (61 , 62) ; however, methylation of these newly discovered CpGs does not block transcription.

A chromatin-mediated mechanism by which DNA methylation may be involved in gene expression is through methylation-dependent chromatin condensation, which creates a structure inaccessible to the transcription machinery. Much research (63 , 64) identifies the presence of methyl groups on DNA as the focus where chromatin condensation is nucleated.

As H1 histone is involved in chromatin compaction, clearly a hypothesis to verify was whether the methylation-dependent chromatin condensation could be explained by a stronger preference of H1 histone for methylated DNA. The literature on this point is highly controversial. H1 has been described as a protein strongly preferring to bind to methylated DNA (65 , 66) , but evidence to the opposite has also been reported (67 68 69) .

To explain the ambiguity of the LH binding studies it is important to remember that H1 histone is not a single molecular entity, but a family of protein variants encoded by five to seven members of the H1 histone gene family in mammals (70) . Some variants (H1a, H1b, H1c, H1d, and H1e) are present in all somatic cells, whereas others (e.g., H5, H1°, H1t, and H1s) are species- and cell type-specific. Even the genes encoding the somatic variants are expressed at significantly different levels depending on the species, tissue, cell-cycle phase, and development stage, so that the relative abundance of each single variant could be different in the H1 histone mixture used in various experiments. This is particularly important if we consider that variants differ in their ability to bind different DNA sequences (71 72 73) .

Despite the ambiguity concerning the effect of DNA methylation on LH binding, the results of Meehan et al. (31) on the binding of another protein, MeCP2, to methylated DNA are highly relevant to the displacement issue considered here. This protein, which binds specifically to methylated DNA (74) , is capable of displacing histone H1 in order to gain access to its preferred binding sites on the methylated template: the binding of MeCP2 exerts a repressive effect on transcription. Thus, MeCP2 can be seen as a closing factor specific for methylated promoters in our activation/repression scenario (see Fig. 1 ).

Recent experiments have identified another role for MeCP2. It has been reported that MeCP2 acts as a shuttle interlocking DNA methylation and core histone deacetylation in inducing gene silencing (75 , 76) . The protein recognizes methylated DNA (77) and transfers onto it the histone deacetylase, which in turn deacetylates the core histones, inducing the methylation-dependent chromatin condensation. In this case, methylated CpGs seem to serve as the recognition feature of the genes to be silenced by the action of histone deacetylases.

But is acetylation (or deacetylation inhibition) enough to activate repressed genes? This question is still open, although some data seem to indicate that the induction of chromatin acetylation is not enough to reactivate repressed genes; in addition, the genes should undergo DNA demethylation before being reactivated (78) .

Thus, the overall picture that emerges from the data discussed above allocates LHs a central position in a complicated network of molecular interactions modulating specific gene expression (Fig. 2 ). The affinity of LH binding to chromatin is inversely related to the ease with which the protein will be displaced, or its binding modified by transcription regulating protein factors. The LH binding affinity is, in turn, a function of postsynthetic modifications of the LH itself and/or of the core histones. Modification (methylation) of the DNA is not a side viewer either; rather, it participates, through protein intermediators in the LH-mediated transcription regulation by either directly affecting H1 displacement by closing factors or by affecting histone acetylation levels, and through them, the affinity of LH binding.

View larger version (33K): [in this window] [in a new window]   Figure 2. Scheme depicting the network of interactions affecting LH binding to chromatin, and hence, gene transcription. The binding of LH is affected by its own postsynthetic modifications, phosphorylation, and poly(ADP-ribosyl)ation by core histone acetylation and, via protein mediators, by DNA methylation. DNA methylation could affect LH binding via two distinct pathways: through LH displacement by methyl-CpG binding proteins or by guiding histone deacetylases, again through methyl-CpG binding proteins to methylated regions; histone deacetylation, in turn, affects LH binding affinity. The text in italics denotes specific findings in specific systems.

	NEW QUESTIONS

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 
Science often advances rapidly when a seminal discovery opens the field to new, previously unphraseable questions. It seems to us that this is happening now in the area of regulation of transcription by chromatin structure. A host of new questions are now posed; we list just a few:

1. Does the DNA sequence at the LH binding site help determine lability of LH binding or does it only influence the strength of competitor binding?
   
2. Do different variants of LHs respond differently to displacement by transcription factors or to modifications such as phosphorylation, which can affect displacement? It seems likely that this is true for extreme variants like H5, but what about the canonical somatic variants of H1, etc.?
   
3. Can core histone sequence variation (in addition to post-translational tail modifications) also influence the stability of LH binding?
   

Questions 2 and 3 ask whether we may finally be approaching the question that has haunted the chromatin field for decades: why are there so many variants and modifications of the histones? Perhaps we have here a key to a gate.

	ACKNOWLEDGMENTS

 
This work was supported in part by TW00568 FIRCA (Fogarty International Research Cooperation Award) (K.v.H. and J.Z.), by the Italian Ministry of University and Scientific and Technological Research, and by the Consiglio Nazionale delle Ricerche (P.C.)

	REFERENCES

TOP ABSTRACT INTRODUCTION LINKER HISTONES AS REGULATORS... LINKER HISTONES ARE GATES... PROTEIN FACTORS THAT CAN... Further levels of regulation... Linker histone phosphorylation Linker histone poly(ADP... Core histone acetylation DNA methylation NEW QUESTIONS REFERENCES

 

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