Effect of CAT or AGG Interruptions and CpG Methylation on Nucleosome Assembly upon Trinucleotide Repeats on Spinocerebellar Ataxia, Type 1 and Fragile X Syndrome*

Nucleosome packaging regulates many aspects of DNA metabolism and is thought to mediate genetic instability and transcription of expanded trinucleotide repeats. Both instability and transcription are sensitive to repeat length, tract purity, and CpG methylation. CAT or AGG interruptions within the (CAG)n or (CGG)n tracts of spinocerebellar ataxia, type 1 or fragile X syndrome, respectively, confer increased genetic stability to the repeats. We report the formation of nucleosomes on sequences containing pure and interrupted (CAG)n and (CGG)n repeats having lengths above and below the genetic stability thresholds. Increased lengths of pure repeats led to increased and decreased propensities for nucleosome assembly on the (CAG)n and (CGG)n repeats, respectively. CpG methylation of the CGG repeat further reduced assembly. CAT interruptions in (CAG)n tracts decreased nucleosome assembly. In contrast, AGG interruptions in (CGG)n tracts did not affect assembly by hypoacetylated histones. The latter observation was unaltered by CpG methylation of the repeats. However, nucleosome assembly by hyperacetylated histones on interrupted CGG tracts was increased relative to pure tracts and this effect was abolished by CpG methylation. Thus, CAT or AGG interruptions can modulate the ability of (CAG)n and (CGG) tracts to assemble into chromatin and the effect of the AGG interruptions is dependent upon both the methylation status of the DNA and the acetylation status of the histones. Compared with the genetically unstable pure repeats, both interruptions permit a propensity of nucleosome assembly closer to that of random (genetically stable) sequences, suggesting an association of nucleosome assembly of trinucleotide repeats and genetic instability. Nucleosome packaging regulates many aspects of DNA metabolism and is thought to mediate genetic instability and transcription of expanded trinucleotide repeats. Both instability and transcription are sensitive to repeat length, tract purity, and CpG methylation. CAT or AGG interruptions within the (CAG)n or (CGG)n tracts of spinocerebellar ataxia, type 1 or fragile X syndrome, respectively, confer increased genetic stability to the repeats. We report the formation of nucleosomes on sequences containing pure and interrupted (CAG)n and (CGG)n repeats having lengths above and below the genetic stability thresholds. Increased lengths of pure repeats led to increased and decreased propensities for nucleosome assembly on the (CAG)n and (CGG)n repeats, respectively. CpG methylation of the CGG repeat further reduced assembly. CAT interruptions in (CAG)n tracts decreased nucleosome assembly. In contrast, AGG interruptions in (CGG)n tracts did not affect assembly by hypoacetylated histones. The latter observation was unaltered by CpG methylation of the repeats. However, nucleosome assembly by hyperacetylated histones on interrupted CGG tracts was increased relative to pure tracts and this effect was abolished by CpG methylation. Thus, CAT or AGG interruptions can modulate the ability of (CAG)n and (CGG) tracts to assemble into chromatin and the effect of the AGG interruptions is dependent upon both the methylation status of the DNA and the acetylation status of the histones. Compared with the genetically unstable pure repeats, both interruptions permit a propensity of nucleosome assembly closer to that of random (genetically stable) sequences, suggesting an association of nucleosome assembly of trinucleotide repeats and genetic instability. The expansion of repeat tracts is associated with at least 42 human diseases (1Cleary J.D. Pearson C.E. Cytogenet. Genome. Res. 2003; 100: 25-55Crossref PubMed Scopus (120) Google Scholar). Although the instability of CAG/CTG repeats is the cause of 12 diseases, six rare chromosomal fragile sites, three of which are disease-associated, are caused by unstable CGG/CCG tracts. In addition to genetic instability, both CAG- and CGG-expanded repeats have been associated with altered transcription regulation and altered chromatin packaging (2Wang Y-H. Amirhaeri S. Kang S. Wells R.D. Griffith J.D. Science. 1994; 265: 669-671Crossref PubMed Scopus (210) Google Scholar, 3Eberhart D.E. Warren S.T. Somat. Cell. Mol. Genet. 1996; 22: 435-441Crossref PubMed Scopus (24) Google Scholar). Genetic instability and transcription of the expanded repeats are modulated by various factors including repeat tract length, repeat tract purity, and aberrant CpG methylation. Mechanistically, the effects of each DNA variable may be transmitted by alterations in histone protein-DNA assembly. However, the interrelation of repeat purity upon nucleosome packaging is unknown. Repeat instability is dependent upon both the length and purity of the repeat tract. Longer alleles are more likely to undergo further expansion than their predecessor alleles. Sequence interruptions within the repeat tracts confer increased genetic stability to the tracts (4Chung M Ranum L.P.W. Duvick L.A. Servadio A. Zoghbi H.Y. Orr H.T. Nat. Genet. 1993; 5: 254-258Crossref PubMed Scopus (432) Google Scholar, 5Chong S.S. McCall A.E. Cota J. Subramony S.H. Orr H.T. Hughes M.R. Zoghbi H.Y. Nat. Genet. 1995; 10: 344-350Crossref PubMed Scopus (165) Google Scholar, 6Eichler E.E. Holden J.J.A. Popovich B.W. Reiss A.L. Snow K. Thibodeau S.N. Richards C.S. Ward P.A. Nelson D.L. Nat. Genet. 1994; 8: 88-94Crossref PubMed Scopus (412) Google Scholar, 7Kunst C.B. Warren S.T. Cell. 1994; 77: 853-861Abstract Full Text PDF PubMed Scopus (320) Google Scholar, 8Zhong N. Yang W. Dobkin C. Brown W.T. Am. J. Hum. Genet. 1995; 57: 351-361PubMed Google Scholar). In non-affected individuals, the (CAG)n tract of spinocerebellar ataxia, type 1 (SCA1) 1The abbreviations used are: SCA1, spinocerebellar ataxia, type 1; FRAXA, fragile X syndrome; nt, nucleotide.1The abbreviations used are: SCA1, spinocerebellar ataxia, type 1; FRAXA, fragile X syndrome; nt, nucleotide. contains 1–3 CAT interruptions, usually centrally located and separated by one CAG (4Chung M Ranum L.P.W. Duvick L.A. Servadio A. Zoghbi H.Y. Orr H.T. Nat. Genet. 1993; 5: 254-258Crossref PubMed Scopus (432) Google Scholar, 5Chong S.S. McCall A.E. Cota J. Subramony S.H. Orr H.T. Hughes M.R. Zoghbi H.Y. Nat. Genet. 1995; 10: 344-350Crossref PubMed Scopus (165) Google Scholar). In the normal population, the (CGG)n tract of fragile X syndrome (FRAXA) contains 1–3 AGG interruptions, typically at every tenth repeat (6Eichler E.E. Holden J.J.A. Popovich B.W. Reiss A.L. Snow K. Thibodeau S.N. Richards C.S. Ward P.A. Nelson D.L. Nat. Genet. 1994; 8: 88-94Crossref PubMed Scopus (412) Google Scholar, 7Kunst C.B. Warren S.T. Cell. 1994; 77: 853-861Abstract Full Text PDF PubMed Scopus (320) Google Scholar, 8Zhong N. Yang W. Dobkin C. Brown W.T. Am. J. Hum. Genet. 1995; 57: 351-361PubMed Google Scholar). Longer lengths of the pure repeats correlate with instability and disease. The stability threshold lengths at which increased instability occurs are ≥35 pure CAG and ≥25–34 pure CGG for SCA1 and FRAXA, respectively (4Chung M Ranum L.P.W. Duvick L.A. Servadio A. Zoghbi H.Y. Orr H.T. Nat. Genet. 1993; 5: 254-258Crossref PubMed Scopus (432) Google Scholar, 5Chong S.S. McCall A.E. Cota J. Subramony S.H. Orr H.T. Hughes M.R. Zoghbi H.Y. Nat. Genet. 1995; 10: 344-350Crossref PubMed Scopus (165) Google Scholar, 6Eichler E.E. Holden J.J.A. Popovich B.W. Reiss A.L. Snow K. Thibodeau S.N. Richards C.S. Ward P.A. Nelson D.L. Nat. Genet. 1994; 8: 88-94Crossref PubMed Scopus (412) Google Scholar, 7Kunst C.B. Warren S.T. Cell. 1994; 77: 853-861Abstract Full Text PDF PubMed Scopus (320) Google Scholar, 8Zhong N. Yang W. Dobkin C. Brown W.T. Am. J. Hum. Genet. 1995; 57: 351-361PubMed Google Scholar). The reasons for the stabilizing effect of the interruptions are not well understood. The limited types of interruptions, CAT and AGG, and the pattern of their placement within the SCA1 and FRAXA repeat tract suggest a degree of specificity in their ability to protect from instability. There have only been a limited number of experimental studies investigating the role of interruptions in repeat instability. Several have used endogenous interruptions and configurations (9Pearson C.E. Eichler E.E. Lorenzetti D. Kramer S.F. Zoghbi H.Y. Nelson D.L. Sinden R.R. Biochemistry. 1998; 37: 2701-2708Crossref PubMed Scopus (134) Google Scholar, 10Maurer D.J. O'Callaghan B.L. Livingston D.M. Mol. Cell. Biol. 1998; 18: 4597-4604Crossref PubMed Scopus (26) Google Scholar), whereas others have used non-typical patterns (11Samadashwily G.M. Raca G. Mirkin S.M. Nat. Genet. 1997; 17: 298-304Crossref PubMed Scopus (282) Google Scholar, 12Rolfsmeier M.L. Lahue R.S. Mol. Cell. Biol. 2000; 20: 173-180Crossref PubMed Scopus (60) Google Scholar, 13Rolfsmeier M.L. Dixon M.J. Lahue R.S. Mol. Cell. 2000; 6: 1501-1507Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). In addition to decreasing the propensity for slipped-strand structure formation (9Pearson C.E. Eichler E.E. Lorenzetti D. Kramer S.F. Zoghbi H.Y. Nelson D.L. Sinden R.R. Biochemistry. 1998; 37: 2701-2708Crossref PubMed Scopus (134) Google Scholar), facilitating replication fork progression (11Samadashwily G.M. Raca G. Mirkin S.M. Nat. Genet. 1997; 17: 298-304Crossref PubMed Scopus (282) Google Scholar), and altering repair of interrupted repeat tracts (13Rolfsmeier M.L. Dixon M.J. Lahue R.S. Mol. Cell. 2000; 6: 1501-1507Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), it has been hypothesized that interruptions may provide genetic stability to the repeat tracts through altered nucleosome conformations (14Metzenberg S. Am. J. Hum. Genet. 1996; 59: 252-253PubMed Google Scholar). Alterations in nucleosome formation can affect various processes including transcription. Expanded CTG/CAG and CGG/CCG repeat tracts have variously been associated with decreased (15Choong C.S. Kemppainen J.A. Zhou Z.X. Wilson E.M. Mol. Endocrinol. 1996; 10: 1527-1535Crossref PubMed Scopus (264) Google Scholar, 16Brooks B.P. Paulson H.L. Merry D.E. Salazar-Grueso E.F. Brinkmann A.O. Wilson E.M. Fischbeck K.H. Neurobiol. Dis. 1997; 3: 313-323Crossref PubMed Scopus (83) Google Scholar), increased (17Tassone F. Hagerman R.J. Chamberlain W.D. Hagerman P.J. Am. J. Med. Genet. 2000; 97: 195-203Crossref PubMed Scopus (166) Google Scholar, 18Kenneson A. Zhang F. Hagedorn C.H. Warren S.T. Hum. Mol. Genet. 2001; 10: 1449-1454Crossref PubMed Scopus (373) Google Scholar), or unaltered (19Krahe R. Ashizawa T. Abbruzzese C. Roeder E. Carango P. Giacanelli M. Funanage V.L. Siciliano M.J. Genomics. 1995; 28: 1-14Crossref PubMed Scopus (128) Google Scholar) transcription rates of the associated or proximal genes. A loss of FMR1 transcription is linked to full CGG expansions (>200 repeats) and aberrant CpG methylation of the repeat and proximal regions (20Hornstra I.K. Nelson D.L. Warren S.T. Yang T.P. Hum. Mol. Genet. 1993; 2: 1659-1665Crossref PubMed Scopus (121) Google Scholar). Interestingly, “premutation” lengths of FRAXA (CGG)n where n = 40–200 displayed increased levels of transcription compared with shorter non-disease-associated lengths of 30 repeats (17Tassone F. Hagerman R.J. Chamberlain W.D. Hagerman P.J. Am. J. Med. Genet. 2000; 97: 195-203Crossref PubMed Scopus (166) Google Scholar, 18Kenneson A. Zhang F. Hagedorn C.H. Warren S.T. Hum. Mol. Genet. 2001; 10: 1449-1454Crossref PubMed Scopus (373) Google Scholar, 21Oostra B.A. Willemsen R. Hum. Mol. Genet. 2003; 12: R249-R257Crossref PubMed Scopus (111) Google Scholar, 22Allen E.G. He W. Yadav-Shah M. Sherman S.L. Hum. Genet. 2004; 114: 439-447Crossref PubMed Scopus (106) Google Scholar). These expanded lengths were also associated with variant sites of transcription initiation (23Beilina A. Tassone F. Schwartz H. Sahota P. Hagerman P.J. Hum. Mol. Genet. 2004; 13: 543-549Crossref PubMed Scopus (67) Google Scholar). Moreover, these premutation lengths were associated with premature ovarian failure (24Murray A. Semin. Reprod. Med. 2000; 18: 59-66Crossref PubMed Scopus (53) Google Scholar) and the recently described fragile X tremor ataxia syndrome (25Hagerman P.J. Hagerman R.J. Am. J. Hum. Genet. 2004; 74: 805-816Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar) that are clinically distinct from FRAXA mental retardation. Altered transcription regulation of genes with expanded repeats is thought to be mediated by altered chromatin packaging at the expanded repeat. Aberrant CpG methylation is associated with CGG instability in addition to affecting FMR1 transcription. In the absence of aberrant CpG methylation, CGG deletions can occur in the male germ line during development of a FRAXA fetus (26Malter H.E. Iber J.C. Willemsen R. de Graaff E. Tarleton J.C. Leisti J. Warren S.T. Oostra B.A. Nat. Genet. 1997; 15: 165-169Crossref PubMed Scopus (168) Google Scholar), whereas the expanded and methylated repeats are postnatally stable. Similarly, the absence of CpG methylation may enhance CGG deletions in the somatic tissues of high functioning FRAXA males that inherited an expanded CGG tract that had experienced only partial aberrant CpG methylation (27Wöhrle D. Salat U. Gläser D. Mücke J. Meisel-Stosiek M. Schindler D. Vogel W. Steinbach P. J. Med. Genet. 1998; 35: 103-111Crossref PubMed Scopus (86) Google Scholar, 28Burman R.W. Popovich B.W. Jacky P.B. Turker M.S. Hum. Mol. Genet. 1999; 8: 2293-2302Crossref PubMed Scopus (32) Google Scholar) There is some suggestion that the effects of CpG methylation on instability are mediated through replication (29Nichol K. Pearson C.E. Genome Res. 2002; 12: 1246-1256Crossref PubMed Scopus (29) Google Scholar). 2K. N. Edamura, M. Leonard, and C. E. Pearson, unpublished data.2K. N. Edamura, M. Leonard, and C. E. Pearson, unpublished data. Modulation of CpG methylation and histone modifications can affect cytogenetic fragile site expression and transcriptional activity at the FRAXA locus. Cytogenetic fra(X)(q27.3) fragile site expression, which is unique to FRAXA patient cells with CGG expansions, can be blocked by histone acetylation/methylation by exposure to butyrate (30Pomponi M.G. Neri G. Am. J. Med. Genet. 1994; 51: 447-450Crossref PubMed Scopus (20) Google Scholar). De-methylation of DNA by 5-azadeoxycytidine can reactivate suppressed FMR1 transcription in FRAXA patient cells (31Chiurazzi P. Pomponi M.G. Willemsen R. Oostra B.A. Neri G. Hum. Mol. Genet. 1998; 7: 109-113Crossref PubMed Scopus (157) Google Scholar, 32Chiurazzi P. Pomponi M.G. Pietrobono R. Bakker C.E. Neri G. Oostra B.A. Hum. Mol. Genet. 1999; 8: 2317-2323Crossref PubMed Scopus (187) Google Scholar). De-methylation is coincident with re-association of acetylated histones at the FMR1 locus (33Coffee B. Zhang F. Warren S.T. Reines D. Nat. Genet. 1999; 22: 98-101Crossref PubMed Scopus (264) Google Scholar, 34Coffee B. Zhang F. Ceman S. Warren S.T. Reines D. Am. J. Hum. Genet. 2002; 71: 923-932Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). In this paper, we examined the effect of repeat interruptions, DNA methylation, and histone acetylation status on the formation of nucleosomes on SCA1 and FRAXA repeats with repeat lengths above and below the genetic stability thresholds. DNA—Genomic containing human SCA1 and and FRAXA and repeat tracts have been to DNA containing repeat lengths and patterns that are within the human The of of the has been described in (9Pearson C.E. Eichler E.E. Lorenzetti D. Kramer S.F. Zoghbi H.Y. Nelson D.L. Sinden R.R. Biochemistry. 1998; 37: 2701-2708Crossref PubMed Scopus (134) Google Scholar, K. Pearson C.E. Genome Res. 2002; 12: 1246-1256Crossref PubMed Scopus (29) Google Scholar). and were with and to DNA and and were with and to DNA and respectively. contains a pure whereas contains CAG repeats interrupted by CAT Similarly, and pure CGG repeats and repeats, whereas and CGG repeats interrupted by AGG repeats interrupted by AGG sequences and repeats interrupted by AGG sequences, of the SCA1 and FRAXA contains human SCA1, these sequences are and of the CAG tract and from number and for FRAXA, these sequences are and of the CGG tract and from number The were with of DNA in the of methylated the above were methylated with in the of The degree of methylation was by to with a a a was from to of the Nucleosome histone were from cells Griffith J.D. Cell. Full Text PDF PubMed Scopus Google Scholar). cells were with butyrate for to hyperacetylated histone of histone was compared with hypoacetylated by an to acetylated histone The ability of DNA to nucleosomes was nucleosome Y-H. Griffith J.D. Genomics. 1995; PubMed Scopus (120) Google Scholar). DNA with were with of hypoacetylated or hyperacetylated histone with of DNA in a containing was reduced to a of The assembly were on at for at to DNA from the were by The of DNA in each was by DNA was in three for each of histone each DNA a assembly was to a in which the did not histone and the DNA was in the including The was by the of DNA in DNA for each The for the was a of The of nucleosome assembly was to the = of DNA in to DNA for of DNA in to DNA for the Y-H. Griffith J.D. U. S. A. 1996; PubMed Scopus Google Scholar, Y-H. Griffith J.D. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Y-H. R. M. Wells R.D. Griffith J.D. J. Mol. Biol. 1996; PubMed Scopus (106) Google Scholar). The for the DNA was The are from at least three CAT Nucleosome on CAG effect of repeat interruptions on nucleosome assembly was by a SCA1 CAG tract containing repeats interrupted by CAT where CAT with a length of pure CAG repeats hypoacetylated histone nucleosomes were upon DNA with the interrupted and pure repeats and compared with a a for nucleosome assembly and the was the of the DNA to DNA and to the from nucleosome assembly Both the pure repeat and the interrupted repeat nucleosomes than the by and respectively. However, nucleosome assembly on the interrupted repeat was reduced by that for the pure repeat = Thus, the of CAT interruptions within a tract of CAG repeats can the ability of an expanded repeat to assemble into However, the propensity of the interrupted tract to nucleosomes was than that of the that interruptions not the of CTG/CAG to assemble into AGG Nucleosome on or CGG the effect of AGG interruptions on the formation of hypoacetylated nucleosomes on FRAXA CGG repeat tract by pure repeat tracts having and repeats with interrupted lengths of and repeats AGG Both and and of the above were for their ability to assemble The assembly of were in of the CGG or methylated or to assemble into nucleosomes relative to the reduced to levels of However, CAG tracts AGG interruptions in CGG tracts did not affect hypoacetylated nucleosome assembly repeats = pure repeats = Similarly, interruptions to affect hypoacetylated nucleosome formation upon CGG tracts = = CpG Nucleosome on and CGG effect of DNA methylation on nucleosome assembly the pure and interrupted CGG repeats was also in compared with each methylated CGG tract a decreased ability to assemble hypoacetylated nucleosomes repeat DNA = = pure repeat DNA = = Thus, decreased nucleosome formation on CGG repeats, of tract repeat AGG Nucleosome on CGG acetylated than histones are to the CGG repeat at the B. Zhang F. Ceman S. Warren S.T. Reines D. Am. J. Hum. Genet. 2002; 71: 923-932Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). we the effect of AGG interruptions on nucleosome formation hyperacetylated histone and the DNA a in hyperacetylated nucleosome formation is by CGG tracts pure repeat = pure repeat = is a increased hyperacetylated nucleosome formation on shorter CGG tracts pure pure and CGG tract length effect was for hyperacetylated not hypoacetylated and FRAXA The used were from human and both human sequences and and repeat tracts that were pure or interruptions in the In the the CAG and CGG repeats are by whereas the CAT and AGG are by In the the CAT and AGG interruptions are and the number is that of the number of CAG or CGG repeats. The length of the human sequences and the are nucleosome of SCA1 with and CAT of a nucleosome DNA and with histones. DNA in the for the in 1–3 histone DNA of the with histone and were described and of of nucleosome assembly. The is by the of DNA in DNA for each The for the was a of DNA was in three and the of DNA in the and DNA was by a nucleosome of FRAXA in the of hyperacetylated histones. of a nucleosome with the of DNA in histone were from cells with of of nucleosome assembly. DNA was in three CpG Increased Nucleosome on CGG above a in hyperacetylated nucleosome formation on CGG repeats containing AGG interruptions compared with pure CGG repeats. We the CGG repeats their ability to assemble into hyperacetylated the nucleosome assembly by the tracts was abolished by = = that the nucleosome formation mediated by AGG interruptions is dependent upon both the acetylation of the histones and upon the of the In this observation that expanded CTG/CAG and CGG/CCG repeats assemble (2Wang Y-H. Amirhaeri S. Kang S. Wells R.D. Griffith J.D. Science. 1994; 265: 669-671Crossref PubMed Scopus (210) Google Scholar, Y-H. Griffith J.D. Genomics. 1995; PubMed Scopus (120) Google Scholar) or Y-H. Griffith J.D. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Y-H. R. M. Wells R.D. Griffith J.D. J. Mol. Biol. 1996; PubMed Scopus (106) Google Scholar) nucleosome we the effect of repeat purity on the ability of these repeats to assemble we that CAT interruptions in SCA1 CAG tracts decreased their nucleosome whereas AGG interruptions in FRAXA CGG tracts increased nucleosome assembly by hyperacetylated which the nucleosome ability of pure CGG repeats. the of repeat interruptions is to the or the repeats to be more random sequences in their ability to assemble into chromatin effects on chromatin structure may permit the interrupted repeats to be to transcription or more random sequences than genetically unstable The effect of AGG interruptions on nucleosome assembly of the CGG repeats has been DNA an (14Metzenberg S. Am. J. Hum. Genet. 1996; 59: 252-253PubMed Google Scholar). and of AGG in the cause of of the CGG and nucleosome assembly. Similarly, are CAT interruptions are within CAG tracts. These may the ability to assemble Interestingly, the tracts of repeats, which the AGG have been to be K. R. DNA Res. 1997; PubMed Scopus Google Scholar) and assemble into nucleosomes A. K. H. R. Res. 2002; PubMed Scopus Google Scholar). The in the ability of repeat tracts to assemble nucleosomes in the or absence of interruptions may be for affect chromatin which have the the unstable chromatin of the in Y-H. M. Griffith J.D. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar) and the of nucleosome formation of DNA Y-H. Griffith J.D. U. S. A. 1996; PubMed Scopus Google Scholar) in by the used in this further that the propensity of nucleosome assembly in can provide into chromatin stability in have been to genetic instability of CAG and CGG repeats in In and the SCA1 and FRAXA containing interrupted repeat tracts are more than containing pure repeats of length (29Nichol K. Pearson C.E. Genome Res. 2002; 12: 1246-1256Crossref PubMed Scopus (29) Google Scholar). N. and C. E. Pearson, unpublished data. the ability of interruptions to the nucleosome assembly of both repeats from to a closer to that of genetically sequences, suggesting a by which nucleosome formation trinucleotide repeats modulate transcriptional activity or genetic stability of these sequences both AGG interruptions and CpG methylation genetic stability of CGG tracts in both and DNA replication the were with methylated or in both the ability to AGG interruptions is only with DNA in the which with the increased nucleosome assembly of interrupted DNA by hyperacetylated histones. We that the of AGG interruptions and the increased ability by interrupted (CGG)n tracts may be FMR1 expression has been to be by chromatin CGG repeats, in a to nucleosome assembly Y-H. Griffith J.D. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Y-H. R. M. Wells R.D. Griffith J.D. J. Mol. Biol. 1996; PubMed Scopus (106) Google Scholar, J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). we have this and it to CGG tracts that are or Alterations in nucleosome assembly mediated by CGG expansions, CpG methylation, and AGG interruptions may modulate chromatin factors and have been to with the FMR1 D. K. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, B. Reines D. Hum. Mol. Genet. 2004; 13: PubMed Scopus Google Scholar). The of to the CGG repeat and the can and the of repeat transcriptional levels or transcription sites of the FMR1 that CGG tracts assemble hyperacetylated nucleosomes more compared with pure repeats, which may suggest that the increased transcription of premutation FRAXA repeat lengths (17Tassone F. Hagerman R.J. Chamberlain W.D. Hagerman P.J. Am. J. Med. Genet. 2000; 97: 195-203Crossref PubMed Scopus (166) Google Scholar, 18Kenneson A. Zhang F. Hagedorn C.H. Warren S.T. Hum. Mol. Genet. 2001; 10: 1449-1454Crossref PubMed Scopus (373) Google Scholar, 22Allen E.G. He W. Yadav-Shah M. Sherman S.L. Hum. Genet. 2004; 114: 439-447Crossref PubMed Scopus (106) Google Scholar) may for interrupted alleles compared with the pure CGG tracts. effects of AGG interruptions may the of the to fragile X tremor ataxia syndrome premature ovarian both of which are associated with premutation CGG of expanded CGG repeats in to fragile X tremor ataxia syndrome R. M. S. J. L.A. M. Tassone F. Hagerman P.J. Oostra B.A. Hum. Mol. Genet. 2003; 12: PubMed Scopus Google Scholar), whereas was in expanded CGG repeats P. Zhang F. Pearson C.E. J.C. K. Warren S.T. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). did not affect nucleosome assembly upon which may the effect of on FMR1 transcriptional The altered nucleosome assembly upon and tracts of FRAXA and SCA1 repeats may their ability to genetically the repeats and may also correlate with altered transcription with

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