Methylation of H3 Lysine 4 at Euchromatin Promotes Sir3p Association with Heterochromatin

Set1p methylates lysine 4 of histone H3 and can activate transcription by recruiting the chromatin-remodeling factor Isw1p. In addition, Lys-4-methylated H3 is required for maintenance of silencing at the telomeres, rDNA, and HML locus in Saccharomyces cerevisiae. The molecular mechanism underlying the role of Set1p in silencing is not known. Here we report that euchromatic methylation of H3 Lys-4 is necessary to maintain silencing at specific heterochromatic sites. Inactivation of Set1p catalytic activity or mutation of H3 Lys-4 leads to decreased binding of the silent information regulator Sir3p at heterochromatic sites. Concomitantly, there is an increase in the amount of Sir3p bound to genes located in subtelomeric regions. Consistent with this result is the finding that in vitro, Sir3p preferentially binds histone H3 tails when methylation is absent at H3 Lys-4, a situation found in heterochromatin. The inability of Sir3p to bind methylated H3 Lys-4 tails suggests a model whereby H3 Lys-4 methylation prevents Sir3p association at euchromatic sites and therefore concentrates Sir3p at unmodified, heterochromatic regions of the genome. Set1p methylates lysine 4 of histone H3 and can activate transcription by recruiting the chromatin-remodeling factor Isw1p. In addition, Lys-4-methylated H3 is required for maintenance of silencing at the telomeres, rDNA, and HML locus in Saccharomyces cerevisiae. The molecular mechanism underlying the role of Set1p in silencing is not known. Here we report that euchromatic methylation of H3 Lys-4 is necessary to maintain silencing at specific heterochromatic sites. Inactivation of Set1p catalytic activity or mutation of H3 Lys-4 leads to decreased binding of the silent information regulator Sir3p at heterochromatic sites. Concomitantly, there is an increase in the amount of Sir3p bound to genes located in subtelomeric regions. Consistent with this result is the finding that in vitro, Sir3p preferentially binds histone H3 tails when methylation is absent at H3 Lys-4, a situation found in heterochromatin. The inability of Sir3p to bind methylated H3 Lys-4 tails suggests a model whereby H3 Lys-4 methylation prevents Sir3p association at euchromatic sites and therefore concentrates Sir3p at unmodified, heterochromatic regions of the genome. Eukaryotic chromatin undergoes global changes in the level of condensation as cells progress from metaphase to interphase. Besides this general tendency, local chromosomal domains present different levels of organization (for review, see Refs. 1Labrador M. Corces V.G. Cell. 2002; 111: 151-154Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar and 2Jackson D.A. Chromosome Res. 2003; 11: 387-401Crossref PubMed Scopus (47) Google Scholar). Heterochromatin was originally identified cytologically as the portion of the genome that remains condensed after the transition from metaphase to interphase. These regions correspond to telomeres and pericentric chromosomal areas and generally localize attached to the perinuclear compartment. Heterochromatic areas tend to be rich in repetitive sequences, low in gene content (although not depleted of them), transcriptionally silent or showing a variegating phenotype, and typically late to replicate. On the other hand, euchromatin, which may be considered the rest of the genome, de-condenses during interphase, contains most of the genes, is active or proficient for transcription, and replicates early. The yeast Saccharomyces cerevisiae undergoes a mild chromosomal condensation prior to mitosis and does not fulfill all the criteria of higher eukaryote heterochromatin. However, telomeres, ribosomal DNA clusters, and mating type loci present many heterochromatic features. For example, ectopic genes inserted into these sites of the genome exhibit a strong reduction in the expression levels compared with their naturally occurring euchromatic locus. This position effect in gene expression reflects differences in the chromatin (for review, see Ref. 3Rusche L.N. Kirchmaier A.L. Rine J. Annu. Rev. Biochem. 2003; 72: 481-516Crossref PubMed Scopus (598) Google Scholar). In S. cerevisiae, the establishment of silencing is controlled by cis-acting factors called “silencers” and trans-acting proteins that bind to these sites (Rap1, Abf1, and the origin of replication complex). A variety of other proteins including Sir2p, Sir3p, Sir4p, histone H3, and histone H4 are necessary for transcriptional silencing (for review, see Ref. 3Rusche L.N. Kirchmaier A.L. Rine J. Annu. Rev. Biochem. 2003; 72: 481-516Crossref PubMed Scopus (598) Google Scholar). The Sir2, Sir3, and Sir4 proteins spread from the silencing initiation site along chromatin by direct binding of Sir3p and Sir4p with the histone H3 and H4 NH2-terminal tails (4Hecht A. Laroche T. Strahl-Bolsinger S. Gasser S.M. Grunstein M. Cell. 1995; 80: 583-592Abstract Full Text PDF PubMed Scopus (697) Google Scholar, 5Hecht A. Strahl-Bolsinger S. Grunstein M. Nature. 1996; 383: 92-96Crossref PubMed Scopus (450) Google Scholar). The pattern of posttranslational modifications exhibited by H3 and H4 is crucial for efficient spreading of the silencing. Nucleosomes at heterochromatic sites are hypoacetylated, and experiments in vitro demonstrate that Sir3p binds with higher affinity to unacetylated H4 amino-terminal peptides than it does to acetylated ones (Lys-5, Lys-8, Lys-12, and mostly Lys-16) (6Carmen A.A. Milne L. Grunstein M. J. Biol. Chem. 2002; 277: 4778-4781Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Notably, the silent information regulator Sir2p is a NAD-dependent histone deacetylase that maintains hypoacetylated nucleosomes at silent sites by antagonizing the histone acetyltransferase activity of Sas2p (7Kimura A. Umehar T. Horikoshi M. Nat. Genet. 2002; 32: 370-377Crossref PubMed Scopus (300) Google Scholar, 8Suka N. Luo K. Grunstein M. Nat. Genet. 2002; 32: 378-383Crossref PubMed Scopus (349) Google Scholar). In addition to Sas2p, other members of the MYST family of acetyltransferases (MOZ, Ybfz/Sas3, Tip60) are involved in silencing in yeasts and higher eukaryotes (for review, see Ref. 9Carrozza M.J. Utley R.T. Workman J.L. Cote J. Trends Genet. 2003; 19: 321-329Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar). The proposed model to explain why acetyltransferases are necessary to maintain silencing is that the heavily acetylated euchromatin creates a suboptimal environment for the silencing complexes to spread by association with the histones H3 and H4. This leads to an accumulation of the silencers at the heterochromatic sites. Loss of histone acetyltransferase activity presumably allows Sir protein complexes to spread further afield, resulting in a reduced amount of these complexes at heterochromatic areas. These lower levels are insufficient for sustaining the repression of transcription (10Kristjuhan A. Wittschieben B.O. Walker J. Roberts D. Cairns B.R. Svejstrup J.Q. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 7551-7556Crossref PubMed Scopus (34) Google Scholar) (for review, see Ref. 11Grunstein M. Curr. Opin. Cell Biol. 1997; 9: 383-387Crossref PubMed Scopus (178) Google Scholar). Histone lysine methylation has also been linked to heterochromatin formation and silencing (for review, see Ref. 12Grewal S.I. Moazed D. Science. 2003; 301: 798-802Crossref PubMed Scopus (787) Google Scholar). The Set1 protein methylates lysine 4 on histone H3 in S. cerevisiae (13Roguev A. Schaft D. Shevchenko A. Pijnappel W.W. Wilm M. Aasland R. Stewart A.F. EMBO J. 2001; 20: 7137-7148Crossref PubMed Scopus (461) Google Scholar, 14Briggs S.D. Bryk M. Strahl B.D. Cheung W.L. Davie J.K. Dent S.Y. Winston F. Allis C.D. Genes Dev. 2001; 15: 3286-3295Crossref PubMed Scopus (481) Google Scholar). This modification fully activates transcription of many genes, in part by facilitating the recruitment of the chromatin-remodeling ATPase Isw1p to chromatin (15Santos-Rosa H. Schneider R. Bannister A.J. Sherriff J. Bernstein B.E. Emre N.C. Schreiber S.L. Mellor J. Kouzarides T. Nature. 2002; 419: 407-411Crossref PubMed Scopus (1608) Google Scholar, 16Santos-Rosa H. Schneider R. Bernstein B.E. Karabetsou N. Morillon A. Weise C. Schreiber S.L. Mellor J. Kouzarides T. Mol. Cell. 2003; 12: 1325-1332Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar). In addition, several groups have reported a role for Set1p in silencing at the rDNA tandem repeats (14Briggs S.D. Bryk M. Strahl B.D. Cheung W.L. Davie J.K. Dent S.Y. Winston F. Allis C.D. Genes Dev. 2001; 15: 3286-3295Crossref PubMed Scopus (481) Google Scholar), telomeres (17Nislow C. Ray E. Pillus L. Mol. Biol. Cell. 1997; 8: 2421-2436Crossref PubMed Scopus (202) Google Scholar, 18Krogan N.J. Dover J. Khorrami S. Greenblatt J.F. Schneider J. Johnston M. Shilatifard A. J. Biol. Chem. 2002; 277: 10753-10755Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar), and the silent copy of the mating type HML (17Nislow C. Ray E. Pillus L. Mol. Biol. Cell. 1997; 8: 2421-2436Crossref PubMed Scopus (202) Google Scholar). Although the role of Set1p in silencing at the rDNA seems to be independent of Sir2p (19Bryk M. Briggs S.D. Strahl B.D. Curcio M.J. Allis C.D. Winston F. Curr. Biol. 2002; 12: 165-170Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar), the amount of Sir2p associated to telomeres is synergistically reduced by mutations on Dot1p (lysine 79 H3 methyltransferase) and Set1p (lysine 4 H3 methyltransferase) (20Ng H.H. Dole S. Struhl K. J. Biol. Chem. 2003; 278: 33625-33628Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). This suggests that methylation at both Lys-4 and Lys-79 contributes to the maintenance of silencing by concentrating silencing proteins at heterochromatic sites (20Ng H.H. Dole S. Struhl K. J. Biol. Chem. 2003; 278: 33625-33628Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, 21Van Leeuwen F. Gafken P.R. Gottschling D.E. Cell. 2002; 109: 745-756Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar). Here, evidence is presented that mutation of the Set1p catalytic site results in a decrease in the amount of Sir3p at several heterochromatic sites, re-distribution of the Sir3p protein in the nucleus, and loss of silencing. In vitro, recombinant Sir3p exhibits a direct binding preference for non-H3 Lys-4-methylated peptides, supporting a model in which silencing complexes cluster at heterochromatic sites by interaction with a hypoacetylated and hypomethylated chromatin. Our results suggest that H3 Lys-4 methylation is necessary at euchromatic areas to maintain silencing at heterochromatic areas. Yeast Strains—The yeast strains are listed in Table I.Table IYeast strains used in this studyYeast strainsReferenceSir3-HA (AYH2.45)Grunstein (5Hecht A. Strahl-Bolsinger S. Grunstein M. Nature. 1996; 383: 92-96Crossref PubMed Scopus (450) Google Scholar)Sir3-HA set1C1068A: isogenic to AYH2.45, set1C1068A::TRP1This studyGFP-Sir3 (DMY784)Moazed (12Grewal S.I. Moazed D. Science. 2003; 301: 798-802Crossref PubMed Scopus (787) Google Scholar)GFP-Sir3 set1C1068A: isogenic to GFP-Sir3, set1C1068A::TRP1This studyUCC7201: adh4::URA3-TEL(VII-L) ura3Δ0Gottschling (21Van Leeuwen F. Gafken P.R. Gottschling D.E. Cell. 2002; 109: 745-756Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar)UCC7277: hmra::URA3 ura3Gottschling (21Van Leeuwen F. Gafken P.R. Gottschling D.E. Cell. 2002; 109: 745-756Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar)UCC7275: hmlα::URA3 ura3Δ0Gottschling (21Van Leeuwen F. Gafken P.R. Gottschling D.E. Cell. 2002; 109: 745-756Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar)UCC7201 set1C1068A: isogenic to UCC7201, set1C1068A::HIS3This studyUCC7277 set1C1068A: isogenic to UCC7277, set1C1068A::HIS3This studyUCC7275 set1C1068A: isogenic to UCC7275, set1C1068A::HIS3This studyUCC8000: chrV::URA3This studyWZY42-F12 hht1-hhf1::LEU2, hht2-hhf2::HIS3, pTRP1-HHT2-HHF2Dent-Roth (29Zhang W. Bone J.R. Edmonson D.G. Turner B.M. Roth S.Y. EMBO J. 1998; 17: 3155-3167Crossref PubMed Scopus (277) Google Scholar)WZY42-F12 K4R H3 isogenic to WZY42 F12, pTRP1-hht2K4R-HHF2Dent-Roth (29Zhang W. Bone J.R. Edmonson D.G. Turner B.M. Roth S.Y. EMBO J. 1998; 17: 3155-3167Crossref PubMed Scopus (277) Google Scholar)WZY42-F12 adh4::URA3-TEL(VII-L)This studyWZY42 F12 K4R H3 adh4::URA3-TEL(VII-L)This study Open table in a new tab Chromatin Immunoprecipitation—Chromatin prepared according to Ref. 28Morillon A. O'Sullivan J. Azad A. Proudfoot N. Mellor J. Science. 2003; 300: 492-495Crossref PubMed Scopus (60) Google Scholar was sonicated to produce fragments of 400–500 bp (determined for each experiment). The following antibodies were used for immunoprecipitation: 3 μl of anti-HA 1The abbreviations used are: HA, hemagglutinin; ChIP, chromatin immunoprecipitation; IP, immunoprecipitation; Ab, antibody; WT, wild type; GFP, green fluorescent protein. antibody (number 1666606, Roche) per ChIP; 2 μl of anti-mono-Me Lys-4, -di-Me Lys-4, and -tri-Me Lys-4 antibody (abCam); 50 μl of Sir3 monoclonal antibody (D. Gottschiling); 3 μl of Pan-anti-acetyl H4 antibody (B. Turner), and 3 μl of anti-acetylated Lys-9/H3 Lys-14 antibody (Upstate). Standard PCR analysis (30–33 cycles) was done on 1:10, 1:20, and 1:50 dilutions of the input, antibody-precipitated DNA, and control without antibody. Real time PCR analysis was performed on an ABI Prism 7000 (ABI) A of yeast DNA 1:10, 1:20, and was done for each the was with the chromatin and and Lys-4 and -tri-Me Lys-4 and and H3 and H4 were done with anti-HA antibody from the PCR was done in and the experiments were in different each a was performed to that the and that the the were also to to the of the A was from the of at dilutions of IP, control or and for the factor when the dilutions a and the PCR was fluorescent are as or is and is antibody. The was than of the the different The used for PCR analysis are on of yeast was performed The were for 3 in at The antibodies used anti-HA (number 1666606, and In the binding of Sir3p to the H3 amino-terminal we peptides to of H3, or at The peptides a at the The of Sir3p was in as a and on reduced The protein was from the and 3 and The H3 NH2-terminal peptides were their to the interaction of cells The cells were in an and with Sir3p were in The Set1p for at and HML at the have reported that Set1p activity is necessary for the transcription of many genes in S. cerevisiae. the role of lysine 4 H3 methylation in we used the This with the Set1p it is for H3 Lys-4 and H. Schneider R. Bernstein B.E. Karabetsou N. Morillon A. Weise C. Schreiber S.L. Mellor J. Kouzarides T. Mol. Cell. 2003; 12: 1325-1332Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar). and strains a at the naturally occurring locus HML and loci were for silencing by their to in that mutation of loss of silencing at the of and This result found with the (17Nislow C. Ray E. Pillus L. Mol. Biol. Cell. 1997; 8: 2421-2436Crossref PubMed Scopus (202) Google Scholar, 18Krogan N.J. Dover J. Khorrami S. Greenblatt J.F. Schneider J. Johnston M. Shilatifard A. J. Biol. Chem. 2002; 277: 10753-10755Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar). silencing at the locus is not by mutation of The different of the HML and silencing has also been reported in to other Rine J. 1997; PubMed Google Scholar, S. Google Scholar). Heterochromatic for H3 Lys-4 and Set1p contributes to we the H3 Lys-4 methylation of the gene located at euchromatic and heterochromatic sites and HML and The pattern of and of H3 Lys-4 found on the and active gene and that the euchromatic site is heterochromatic sites were The level of methylation was to the of that the of H3 Lys-4 methylation in heterochromatin is not required for gene silencing. further the H3 Lys-4 methylation levels at several nucleosomes from to of the gene were methylation was found at the heterochromatic in to the accumulation of methylated H3 Lys-4 at the of the euchromatic gene H.H. F. Struhl K. Mol. Cell. 2003; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). These results that silencing in heterochromatin is not a result of Set1p activity on the silent sites. Set1p activates transcription of many genes, we the in silencing in the was to a general decrease in the levels of silencing in the levels of Sir2p, Sir4p, and were in of and isogenic Set1p does not to silencing by the expression of the silencing of the Sir3p at Heterochromatic has been reported that mutations in the for of H3 and as as methylation of H3 silencing by the amount of Sir proteins at the heterochromatic sites (10Kristjuhan A. Wittschieben B.O. Walker J. Roberts D. Cairns B.R. Svejstrup J.Q. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 7551-7556Crossref PubMed Scopus (34) Google Scholar, H.H. Dole S. Struhl K. J. Biol. Chem. 2003; 278: 33625-33628Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, 21Van Leeuwen F. Gafken P.R. Gottschling D.E. Cell. 2002; 109: 745-756Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar). The model is that H3 and H4 H4 Lys-16) and H3 Lys-79 a suboptimal environment for the Sir3 and Sir4 proteins to The silencing factors are therefore to heterochromatic which are hypoacetylated and hypomethylated at to this is the for H3 Lys-4 Sir3p was it is necessary for the spreading of silencing direct interaction with the amino-terminal tails of histones H3 and H4 (4Hecht A. Laroche T. Strahl-Bolsinger S. Gasser S.M. Grunstein M. Cell. 1995; 80: 583-592Abstract Full Text PDF PubMed Scopus (697) Google Scholar). a the amount of Sir3p was at the euchromatic which has been to bind the Sir3p protein D. Nat. Genet. 2001; PubMed Scopus Google Scholar). The amount of Sir3p found at was a of Sir3p was at heterochromatic sites to the amount at or euchromatic The analysis of a and an isogenic a reduction in the amount of Sir3p bound to which decreased on the heterochromatic site However, at heterochromatic the a reduction was not This was with finding that silencing at does not on Set1p the of Sir3p bound to the HML site and to the were also reduced in an H3 K4R with to the isogenic and In in the binding of Sir3p at the site was is that the binding of Sir3p to heterochromatic sites is in the than in the H3 K4R with the that the H3 K4R mutation silencing not This may be the Set1p is in the compared with the H3 K4R that in the other members of the may to Sir3p H3 the K4R mutation may not bind Sir3p as as H3, this binding is than to methylated H3 This result in a of Sir3p from heterochromatic areas in the H3 K4R than the The decrease in the amount of Sir3p bound to with an increase of Sir3p on a subtelomeric gene located a subtelomeric gene located from the of a increase in Sir3p mutation of This suggests that the of H3 Lys-4 methylation allows Sir3p to spread of the heterochromatic regions. A increase in the amount of Sir3p at euchromatic loci (for and not was not the amount of Sir3p in the The of Set1p in of in or H3 Lys-79 was that the effect of in Sir3p may have from changes in H3 H4 which in have the interaction of Sir3p with histones at heterochromatic sites. this was performed with antibodies specific for acetylated H4 anti-acetylated and acetylated H3 and The levels of H3 and H4 at euchromatic and heterochromatic sites were in and the and the effect of Set1p in silencing does not to be by histone the amount of Dot1p in the therefore of H3 was the amount of Dot1p by the global genome levels of H3 Lys-79 methylation were by the mutation not In addition, it has been reported that a a Sir2p at heterochromatin with to the strains supporting for Set1p and Dot1p in the maintenance of silencing (20Ng H.H. Dole S. Struhl K. J. Biol. Chem. 2003; 278: 33625-33628Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). that the role of Set1p in silencing is linked to the H3 Lys-4 activity of of the in Sir3p Sir3p in the to a pattern of perinuclear These an accumulation of Sir3p at the telomeres of F. Laroche T. E. A. Pillus L. Gasser S.M. Cell. Full Text PDF PubMed Scopus Google Scholar). in several genes that silencing the of Sir3p T. M. Gasser S.M. Curr. Biol. 1998; 8: Full Text Full Text PDF PubMed Google Scholar). a decrease in the binding of Sir3p was at telomeres of and in the we the of a protein in the that the perinuclear Sir3p in a is by a that to the in with the mutation the of Sir3p in of Sir3p the on was that the silencing in the be by of this the was the control of the and the protein from a was in the is in silencing at the when on of However, the silencing is when the is with a of and as the This a model for H3 Lys-4 methylation silencing by concentrating the Sir proteins at heterochromatic sites. Lys-4 of Sir3 to the of H3 in has been that the of Sir3p binds to the or NH2-terminal of histone H3 (4Hecht A. Laroche T. Strahl-Bolsinger S. Gasser S.M. Grunstein M. Cell. 1995; 80: 583-592Abstract Full Text PDF PubMed Scopus (697) Google Scholar, 5Hecht A. Strahl-Bolsinger S. Grunstein M. Nature. 1996; 383: 92-96Crossref PubMed Scopus (450) Google Scholar). mechanism by which H3 Lys-4 methylation Sir3 from euchromatin binding to heterochromatin be by direct of Sir3p binding to histone H3 was used to methylation of H3 Lys-4 binding of Sir3p to H3 The of Sir3p bound with a higher affinity to H3 than to peptides at Lys-4 This interaction to be bound Sir3p methylation at H3 Lys-4 Sir3p which is with that the in of Sir3p is when H3 Lys-4 methylation is have reported that mutations of the H3 Lys-4 Set1p silencing at different heterochromatic (14Briggs S.D. Bryk M. Strahl B.D. Cheung W.L. Davie J.K. Dent S.Y. Winston F. Allis C.D. Genes Dev. 2001; 15: 3286-3295Crossref PubMed Scopus (481) Google Scholar, C. Ray E. Pillus L. Mol. Biol. Cell. 1997; 8: 2421-2436Crossref PubMed Scopus (202) Google Scholar, 18Krogan N.J. Dover J. Khorrami S. Greenblatt J.F. Schneider J. Johnston M. Shilatifard A. J. Biol. Chem. 2002; 277: 10753-10755Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar). The molecular underlying these Here it is that yeast methylation of H3 Lys-4 in silencing at several heterochromatic sites by the amount of the silent information regulator protein Sir3p at these heterochromatic an increase in the amount of Sir3p at subtelomeric loci is which suggests that Sir3p of the heterochromatic The direct silencing and H3 Lys-4 methylation from the silencing in the Set1p can be by of H3 Lys-4 methylation is to the direct association of Sir3p with histone H3 In addition to on Sir3p, it has been reported that there is a mild decrease in the amount of Sir2p at telomeres in H3 Lys-4 strains (20Ng H.H. Dole S. Struhl K. J. Biol. Chem. 2003; 278: 33625-33628Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). This effect is with a of H3 Lys-79 methylation with to the amount of Sir2p bound to A was in the association of Sir3p with heterochromatin in the than that for Sir2p in the for (20Ng H.H. Dole S. Struhl K. J. Biol. Chem. 2003; 278: 33625-33628Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). This differences in the affinity of Sir3p and Sir4p Sir2p to for methylated H3 Lys-4, the of Sir4p and or differences to the of a in the the of the as in the In these results suggest that the Sir proteins a higher affinity for histones methylated as is the for acetylated histones (5Hecht A. Strahl-Bolsinger S. Grunstein M. Nature. 1996; 383: 92-96Crossref PubMed Scopus (450) Google Scholar, A.A. Milne L. Grunstein M. J. Biol. Chem. 2002; 277: 4778-4781Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). we a loss of interaction H3 Lys-4-methylated amino-terminal tails and recombinant Sir3p in the of or histones in euchromatic areas may silencing factors from spreading of heterochromatic sites. This be a mechanism to maintain silent domains of chromatin in S. cerevisiae, which modifications specific to heterochromatin as H3 methylation and DNA Turner for the antibody and D. and S. for the antibody. also D. Gottschling and F. Leeuwen for the monoclonal antibody and for several yeast are to S. Dent Roth for the WZY42 F12 and the WZY42 F12 H3

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