Site-specific Binding Affinities within the H2B Tail Domain Indicate Specific Effects of Lysine Acetylation

Acetylation of specific lysines within the core histone tail domains plays a critical role in regulating chromatin-based activities. However, the structures and interactions of the tail domains and the molecular mechanisms by which acetylation directly alters chromatin structures are not well understood. To address these issues we developed a chemical method to quantitatively determine binding affinities of specific regions within the individual tail domains in model chromatin complexes. Examinations of specific sites within the H2B tail domain indicate that this tail contains distinct structural elements and binds within nucleosomes with affinities that would reduce the activity of tail-binding proteins 10–50-fold from that deduced from peptide binding studies. Moreover, we find that mutations mimicking lysine acetylation do not cause a global weakening of tail-DNA interactions but rather the results suggest that acetylation leads to a much more subtle and specific alteration in tail interactions than has been assumed. In addition, we provide evidence that acetylation at specific sites in the tail is not additive with several events resulting in similar, localized changes in tail binding. Acetylation of specific lysines within the core histone tail domains plays a critical role in regulating chromatin-based activities. However, the structures and interactions of the tail domains and the molecular mechanisms by which acetylation directly alters chromatin structures are not well understood. To address these issues we developed a chemical method to quantitatively determine binding affinities of specific regions within the individual tail domains in model chromatin complexes. Examinations of specific sites within the H2B tail domain indicate that this tail contains distinct structural elements and binds within nucleosomes with affinities that would reduce the activity of tail-binding proteins 10–50-fold from that deduced from peptide binding studies. Moreover, we find that mutations mimicking lysine acetylation do not cause a global weakening of tail-DNA interactions but rather the results suggest that acetylation leads to a much more subtle and specific alteration in tail interactions than has been assumed. In addition, we provide evidence that acetylation at specific sites in the tail is not additive with several events resulting in similar, localized changes in tail binding. Nucleosomes are the fundamental repeating subunits of eukaryotic chromatin, comprising about 200 bp of DNA each, 147 bp of which are wrapped about 1.65 times around an octamer of the four core histone proteins (1Luger K. Mader A.W. Richmond R.K. Sargent D.F. Richmond T.J. Nature. 1997; 389: 251-260Crossref PubMed Scopus (6885) Google Scholar, 2Holde K.E. Chromatin. 1989; (Springer-Verlag Inc., New York)Crossref Google Scholar). Strings of nucleosomes are assembled into secondary structures such as the 30 nm diameter chromatin fiber and the higher order tertiary structures perhaps exemplified by the ∼400 nm chromonema fibers (3Thoma F. Koller T. Klug A. J. Cell Biol. 1979; 83: 403-427Crossref PubMed Scopus (1179) Google Scholar, 4Woodcock C.L. Dimitrov S. Curr. Opin. Genet. Dev. 2001; 11: 130-135Crossref PubMed Scopus (221) Google Scholar, 5Hansen J.C. Annu. Rev. Biophys. Biomol. Struct. 2002; 31: 361-392Crossref PubMed Scopus (419) Google Scholar, 6Belmont A.S. Bruce K. J. Cell Biol. 1994; 127: 287-302Crossref PubMed Scopus (277) Google Scholar). The organization of nucleosomes within secondary and tertiary chromatin structures and the molecular interactions responsible for their formation are poorly understood (4Woodcock C.L. Dimitrov S. Curr. Opin. Genet. Dev. 2001; 11: 130-135Crossref PubMed Scopus (221) Google Scholar, 7Dorigo B. Schalch T. Kulangara A. Duda S. Schroeder R.R. Richmond T.J. Science. 2004; 306: 1571-1573Crossref PubMed Scopus (426) Google Scholar, 8Schalch T. Duda S. Sargent D.F. Richmond T.J. Nature. 2005; 436: 138-141Crossref PubMed Scopus (594) Google Scholar). Approximately 75% of the mass of each of the core histones is organized into a largely α-helical domain that is assembled into the protein spool onto which the DNA is wrapped (1Luger K. Mader A.W. Richmond R.K. Sargent D.F. Richmond T.J. Nature. 1997; 389: 251-260Crossref PubMed Scopus (6885) Google Scholar, 9Arents G. Burlingame R.W. Wang B.C. Love W.E. Moudrianakis E.N. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 10148-10152Crossref PubMed Scopus (605) Google Scholar). The remaining mass is contained with the core histone tail domains, which project out from the interior of the nucleosome core and are accessible to both DNA and protein targets in chromatin (10Fletcher T.M. Hansen J.C. J. Biol. Chem. 1995; 270: 25359-25362Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 11Bohm L. Crane-Robinson C. Biosci. Rep. 1984; 4: 365-386Crossref PubMed Scopus (130) Google Scholar, 12Becker P.B. Nature. 2006; 442: 31-32Crossref PubMed Scopus (26) Google Scholar). The tails are essential for formation of higher order secondary and tertiary chromatin structures and participate in short and long range inter-nucleosome interactions (5Hansen J.C. Annu. Rev. Biophys. Biomol. Struct. 2002; 31: 361-392Crossref PubMed Scopus (419) Google Scholar, 7Dorigo B. Schalch T. Kulangara A. Duda S. Schroeder R.R. Richmond T.J. Science. 2004; 306: 1571-1573Crossref PubMed Scopus (426) Google Scholar, 13Kan P.Y. Lu X. Hansen J.C. Hayes J.J. Mol. Cell. Biol. 2007; 27: 2084-2091Crossref PubMed Scopus (91) Google Scholar, 14Zheng C. Lu X. Hansen J.C. Hayes J.J. J. Biol. Chem. 2005; 280: 33552-33557Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Although the tails adopt random coil conformations when released from their binding sites in moderate ionic strength solutions (>0.4 m NaCl) (15Cary P.D. Moss T. Bradbury E.M. Eur. J. Biochem. 1978; 89: 475-482Crossref PubMed Scopus (119) Google Scholar, 16Hilliard Jr., P.R. Smith R.M. Rill R.L. J. Biol. Chem. 1986; 261: 5992-5998Abstract Full Text PDF PubMed Google Scholar, 17Walker I.O. Biochemistry. 1984; 23: 5622-5628Crossref PubMed Scopus (65) Google Scholar, 18Smith R.M. Rill R.L. J. Biol. Chem. 1989; 264: 10574-10581Abstract Full Text PDF PubMed Google Scholar) and are often referred to as “unstructured” domains, evidence suggests they adopt defined structures and make localized interactions when bound within chromatin (19Wang X. Moore S.C. Laszckzak M. Ausio J. J. Biol. Chem. 2000; 275: 35013-35020Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 20Baneres J.L. Martin A. Parello J. J. Mol. Biol. 1997; 273: 503-508Crossref PubMed Scopus (76) Google Scholar, 21Lee K.M. Hayes J.J. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8959-8964Crossref PubMed Scopus (51) Google Scholar, 22Lee K.M. Hayes J.J. Biochemistry. 1998; 37: 8622-8628Crossref PubMed Scopus (53) Google Scholar, 23Zheng C. Hayes J.J. J. Biol. Chem. 2003; 278: 24217-24224Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). For example, a specific interaction between a region within the H4 tail domain and a charged surface formed by the H2A/H2B histone fold domains contributes to stability of the folded chromatin fiber (1Luger K. Mader A.W. Richmond R.K. Sargent D.F. Richmond T.J. Nature. 1997; 389: 251-260Crossref PubMed Scopus (6885) Google Scholar, 7Dorigo B. Schalch T. Kulangara A. Duda S. Schroeder R.R. Richmond T.J. Science. 2004; 306: 1571-1573Crossref PubMed Scopus (426) Google Scholar, 24Shogren-Knaak M. Ishii H. Sun J.M. Pazin M.J. Davie J.R. Peterson C.L. Science. 2006; 311: 844-847Crossref PubMed Scopus (1385) Google Scholar). However, in general the structures and interactions of the tail domains are poorly understood. The core histone tail domains play key roles in the epigenetic regulation of gene expression, and post-translational modifications such as acetylation of specific lysines within these domains are closely linked to transcriptionally active regions of the genome (25Allfrey V.G. Faulkner R. Mirsky A.E. Proc. Natl. Acad. Sci. U. S. A. 1964; 51: 786-794Crossref PubMed Scopus (1747) Google Scholar, M. Nature. 1997; 389: PubMed Scopus Google Scholar, Science. 2000; PubMed Scopus Google Scholar). acetylation as an epigenetic the of to specific to Nature. 2000; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar). In addition, acetylation within the tail domains directly alters the of DNA and the of nucleosome to into higher order structures (5Hansen J.C. Annu. Rev. Biophys. Biomol. Struct. 2002; 31: 361-392Crossref PubMed Scopus (419) Google Scholar, Hayes J.J. Cell. Full Text PDF PubMed Scopus Google Scholar, M. Crane-Robinson C. J.L. J. PubMed Scopus Google Scholar, C. T. Hansen J.C. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar, M. C. Ausio J. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, M.J. Davie J.R. J. Biol. Chem. Full Text PDF PubMed Google Scholar). However, the by which lysine acetylation directly alters the and of chromatin Acetylation results in of the and is often that acetylation resulting in a more and transcriptionally chromatin P.D. Crane-Robinson C. Bradbury E.M. Eur. J. Biochem. 127: PubMed Scopus (65) Google Scholar, L. Bradbury E.M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). However, evidence suggests that the of acetylation much more For example, acetylation of lysine within the H4 tail domain an interaction between the H4 tail and a surface of resulting in a in the of nucleosome to into higher order structures M. Ishii H. Sun J.M. Pazin M.J. Davie J.R. Peterson C.L. Science. 2006; 311: 844-847Crossref PubMed Scopus (1385) Google Scholar). Moreover, and with nucleosomes indicate that acetylation not to a in histone tail-DNA interactions Ausio J. J. Dimitrov S. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar) and about an in the α-helical of the tails (19Wang X. Moore S.C. Laszckzak M. Ausio J. J. Biol. Chem. 2000; 275: 35013-35020Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). suggest that the of acetylation of nucleosome is with a (19Wang X. Moore S.C. Laszckzak M. Ausio J. J. Biol. Chem. 2000; 275: 35013-35020Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 20Baneres J.L. Martin A. Parello J. J. Mol. 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Biol. 1995; PubMed Scopus Google Scholar) as in the defined as in the of we is times higher than that of as a and in which the is defined as in the for the is and the as in and that the of with by as in we are for J. J. Mol. Biol. 1995; PubMed Scopus Google Scholar, J. R.L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). is in In this is to which is to the is in as than for For we find that is to the in the the of to these For this is is that the of the at is from and we and by we and in the we that the of of the with is to the of for the H2A/H2B the of and tail domains Jr., P.R. Smith R.M. Rill R.L. J. Biol. Chem. 1986; 261: 5992-5998Abstract Full Text PDF PubMed Google Scholar, 18Smith R.M. Rill R.L. J. Biol. Chem. 1989; 264: 10574-10581Abstract Full Text PDF PubMed Google Scholar). we find that the of of the and the at the tails are to released from binding sites within nucleosomes I.O. 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Martin A. Parello J. J. Mol. Biol. 1997; 273: 503-508Crossref PubMed Scopus (76) Google Scholar). Moreover, from and indicate ionic within the H2B tail with a of the region of the tail L. Biochemistry. 1997; PubMed Scopus Google Scholar). the general of the tails as domains, these provide for the that the tails adopt defined structures and participate in localized interactions when bound within chromatin C. Hayes J.J. 2003; PubMed Scopus Google Scholar, X. Hayes J.J. Biochem. Cell Biol. 2006; PubMed Google Scholar) Although lysine acetylation is linked to chromatin and is to cause in the of the chromatin fiber (5Hansen J.C. Annu. Rev. Biophys. Biomol. Struct. 2002; 31: 361-392Crossref PubMed Scopus (419) Google is of the molecular by which this alters tail-DNA Although is often that the of this is a general weakening of histone tail-DNA we that mutations acetylation events do not in a weakening of tail binding with Ausio J. J. Dimitrov S. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). suggest that acetylation localized changes in H2B tail For mutations and interactions of both of the H2B but in a weakening of interactions in the of the tail by in by (19Wang X. Moore S.C. Laszckzak M. Ausio J. J. Biol. Chem. 2000; 275: 35013-35020Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). suggest that the of acetylation chromatin is from a much more subtle and specific alteration in tail interaction than has been assumed. find that the of with within the H2B tail domain by a is that in regions sites and and in the range of ionic strength is more than is more than to for the bound and of than and the tail in the of the would for to to specific sites within the tail results that binding of such would by 10–50-fold with binding affinities with the tail domains Wang S. Dev. 2003; PubMed Scopus Google Scholar). such make interactions with sites in the affinities Hansen J.C. S. J.M. 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Biol. 1998; PubMed Scopus Google Scholar) binding of changes in we a in for the of the tail domain of mutations the of tail domains in this region in the bound would from to in the range of with in the of acetylation is in tail domains, is not that to the bound would not an alteration in the of tails bound to DNA of indicate that acetylation events not additive in of structural changes in tail binding by this that at lysines and as much in tail binding interactions as within the H2B tail results provide a structural for results that of four specific lysine acetylation events within the H4 tail domain not to in of global gene in Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar). The of histone tail binding and in (15Cary P.D. Moss T. Bradbury E.M. Eur. J. Biochem. 1978; 89: 475-482Crossref PubMed Scopus (119) Google Scholar, 16Hilliard Jr., P.R. Smith R.M. Rill R.L. J. Biol. Chem. 1986; 261: 5992-5998Abstract Full Text PDF PubMed Google Scholar, 17Walker I.O. Biochemistry. 1984; 23: 5622-5628Crossref PubMed Scopus (65) Google Scholar, 18Smith R.M. Rill R.L. J. Biol. Chem. 1989; 264: 10574-10581Abstract Full Text PDF PubMed Google Scholar) that a of the binding of the H2B tail domain is by between and However, indicate For we find that of of the charged lysines in the H2B tail not to a of tail binding. Moreover, of lysines to not in in at of the sites an H2B tail domain of charged for the binding to sites within the Moreover, in tail binding at sites between tails with and with a H4 tail domain that acetylation binding of an H4 tail peptide to DNA (15Cary P.D. Moss T. Bradbury E.M. Eur. J. Biochem. 1978; 89: 475-482Crossref PubMed Scopus (119) Google Scholar, L. Bradbury E.M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). results indicate that the tail binding in the of chromatin is from the binding of and that than lysine participate in interactions that to tail binding In addition, is that interactions for of lysine and that secondary in participate in interactions within as is in lysine acetylation and in changes to in the H4 tail Wang and J. J. results suggest that lysine not as to tail binding as has been perhaps of a of the and to the of a charged In of these in to the of lysine to within the H2B tail domain the has and a more charged and to more to the binding of the tail domain than In we for the the binding of a core histone tail at specific sites within the tail domain a range of indicate that the tail contains distinct structural domains and binds with affinities as to cause in the activity of tail-binding proteins deduced from peptide binding studies. Moreover, results suggest that acetylation not a general weakening of tail-DNA interactions as is often but rather localized in tail binding. to specific structural changes in tail by (19Wang X. Moore S.C. Laszckzak M. Ausio J. J. Biol. Chem. 2000; 275: 35013-35020Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, X. Hayes J.J. Biochem. Cell Biol. 2006; PubMed Google Scholar). evidence that acetylation events in the H2B tail domain are not additive and not with to structural events the with to binding of the of the changes do not a alteration in binding results with nucleosomes DNA and nucleosome suggest that the H2B tail binds with of the of DNA J.M. Dimitrov S. Hayes J.J. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). to acetylation of DNA distinct changes in tail interactions of the tail domains within the nucleosome acetylation within tail binding of with