Context-dependent Dysregulation of Transcription by Mutant Huntingtin

Huntington disease (HD) is an adult-onset neurodegenerative disease caused by expansion of a polyglutamine (poly(Q) tract in the N-terminal region of huntingtin (htt). Although the precise mechanisms leading to neurodegeneration in HD have not been fully elucidated, transcriptional dysregulation has been implicated in disease pathogenesis. In HD, multiple N-terminal mutant htt fragments smaller than the first 500 amino acids have been found to accumulate in the nucleus and adversely affect gene transcription. It is unknown whether different htt fragments in the nucleus can differentially bind transcription factors and affect transcription. Here, we report that shorter N-terminal htt fragments, which are more prone to misfolding and aggregation, are more competent to bind Sp1 and inhibit its activity. These effects can be reversed by Hsp40, a molecular chaperone that reduces the misfolding of mutant htt. Our results provide insight into the beneficial effects of molecular chaperones and suggest that context dependent transcriptional dysregulation may contribute to differential toxicity of various N-terminal htt fragments. Huntington disease (HD) is an adult-onset neurodegenerative disease caused by expansion of a polyglutamine (poly(Q) tract in the N-terminal region of huntingtin (htt). Although the precise mechanisms leading to neurodegeneration in HD have not been fully elucidated, transcriptional dysregulation has been implicated in disease pathogenesis. In HD, multiple N-terminal mutant htt fragments smaller than the first 500 amino acids have been found to accumulate in the nucleus and adversely affect gene transcription. It is unknown whether different htt fragments in the nucleus can differentially bind transcription factors and affect transcription. Here, we report that shorter N-terminal htt fragments, which are more prone to misfolding and aggregation, are more competent to bind Sp1 and inhibit its activity. These effects can be reversed by Hsp40, a molecular chaperone that reduces the misfolding of mutant htt. Our results provide insight into the beneficial effects of molecular chaperones and suggest that context dependent transcriptional dysregulation may contribute to differential toxicity of various N-terminal htt fragments. Huntington disease (HD) 3The abbreviations used are: HD, Huntington disease; htt, huntingtin; poly(Q), polyglutamine; Hsp, heat shock protein; NLS, nuclear localization sequences; NGFR, nerve growth factor receptor; HEK293, human embryonic kidney 293; PBS, phosphate-buffered saline; DsRed, red fluorescent protein. is an autosomal dominant neurodegenerative disorder resulting from expansion (>37 repeats) of a polyglutamine (poly(Q)) repeat in the N-terminal region of huntingtin (htt), a 350-kDa protein of unknown function. Proteolytic cleavage of full-length htt, which is predominantly cytoplasmic, generates N-terminal htt fragments that accumulate abnormally and form inclusions over time in neuronal nuclei (1DiFiglia M. Sapp E. Chase K.O. Davies S.W. Bates G.P. Vonsattel J.P. Aronin N. Science. 1997; 277: 1990-1993Crossref PubMed Scopus (2331) Google Scholar). The nucleus is thought to be a primary site of poly(Q) toxicity, as blocking the nuclear entry of htt suppresses its ability to cause cell death (2Saudou F. Finkbeiner S. Devys D. Greenberg M.E. Cell. 1998; 95: 55-66Abstract Full Text Full Text PDF PubMed Scopus (1371) Google Scholar), whereas targeting htt to the nucleus by the addition of a nuclear localization signal (NLS) causes a more severe phenotype (3Peters M.F. Nucifora F.C. Kushi Jr., J. Seaman H.C. Cooper J.K. Herring W.J. Dawson V.L. Dawson T.M. Ross C.A. Mol. Cell Neurosci. 1999; 14: 121-128Crossref PubMed Scopus (170) Google Scholar, 4Schilling G. Savonenko A.V. Klevytska A. Morton J.L. Tucker S.M. Poirier M. Gale A. Chan N. Gonzales V. Slunt H.H. Coonfield M.L. Jenkins N.A. Copeland N.G. Ross C.A. Borchelt D.R. Hum. Mol. Genet. 2004; 13: 1599-1610Crossref PubMed Scopus (85) Google Scholar, 5Benn C.L. Landles C. Li H. Strand A.D. Woodman B. Sathasivam K. Li S.H. Ghazi-Noori S. Hockly E. Faruque S.M. Cha J.H. Sharpe P.T. Olson J.M. Li X.J. Bates G.P. Hum. Mol. Genet. 2005; 14: 3065-3078Crossref PubMed Scopus (96) Google Scholar). In the nucleus, mutant htt abnormally interacts with a number of transcription factors (6Li S.H. Li X.J. Trends Genet. 2004; 20: 146-154Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). Accordingly, the nuclear pathology observed in HD is thought to be largely due to transcriptional dysregulation (7Cha J.H. Trends Neurosci. 2000; 23: 387-392Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar, 8Sugars K.L. Rubinsztein D.C. Trends Genet. 2003; 19: 233-238Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar). In fact, mRNA levels are altered for specific genes in HD mouse and cell models as well as in post-mortem human HD brain (7Cha J.H. Trends Neurosci. 2000; 23: 387-392Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar, 8Sugars K.L. Rubinsztein D.C. Trends Genet. 2003; 19: 233-238Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar, 9Li S.H. Cheng A.L. Li H. Li X.J. J. Neurosci. 1999; 19: 5159-5172Crossref PubMed Google Scholar, 10Luthi-Carter R. Strand A.D. Hanson S.A. Kooperberg C. Schilling G. La Spada A.R. Merry D.E. Young A.B. Ross C.A. Borchelt D.R. Olson J.M. Hum. Mol. Genet. 2002; 11: 1927-1937Crossref PubMed Google Scholar, 11Sipione S. Rigamonti D. Valenza M. Zuccato C. Conti L. Pritchard J. Kooperberg C. Olson J.M. Cattaneo E. Hum. Mol. Genet. 2002; 11: 1953-1965Crossref PubMed Google Scholar). Mutant htt has a higher affinity than normal htt for certain transcription factors, such as Sp1 (12Li S.H. Cheng A.L. Zhou H. Lam S. Rao M. Li H. Li X.J. Mol. Cell. Biol. 2002; 22: 1277-1287Crossref PubMed Scopus (284) Google Scholar, 13Chen-Plotkin A.S. Sadri-Vakili G. Yohrling G.J. Braveman M.W. Benn C.L. Glajch K.E. Dirocco D.P. Farrell L.A. Krainc D. Gines S. Macdonald M.E. Cha J.H. Neurobiol. Dis. 2006; 22: 233-241Crossref PubMed Scopus (89) Google Scholar, 14Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (588) Google Scholar, 15Zhai W. Jeong H. Cui L. Krainc D. Tjian R. Cell. 2005; 123: 1241-1253Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar), and these aberrant interactions can functionally deactivate transcription factors by titrating them away from their normal DNA binding sites (12Li S.H. Cheng A.L. Zhou H. Lam S. Rao M. Li H. Li X.J. Mol. Cell. Biol. 2002; 22: 1277-1287Crossref PubMed Scopus (284) Google Scholar, 13Chen-Plotkin A.S. Sadri-Vakili G. Yohrling G.J. Braveman M.W. Benn C.L. Glajch K.E. Dirocco D.P. Farrell L.A. Krainc D. Gines S. Macdonald M.E. Cha J.H. Neurobiol. Dis. 2006; 22: 233-241Crossref PubMed Scopus (89) Google Scholar, 14Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (588) Google Scholar, 15Zhai W. Jeong H. Cui L. Krainc D. Tjian R. Cell. 2005; 123: 1241-1253Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 16Schaffar G. Breuer P. Boteva R. Behrends C. Tzvetkov N. Strippel N. Sakahira H. Siegers K. Hayer-Hartl M. Hartl F.U. Mol. Cell. 2004; 15: 95-105Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar). Biochemical analysis of HD knock-in mice that express a 150-glutamine repeat in the endogenous mouse htt (17Lin C.H. Tallaksen-Greene S. Chien W.M. Cearley J.A. Jackson W.S. Crouse A.B. Ren S. Li X.J. Albin R.L. Detloff P.J. Hum. Mol. Genet. 2001; 10: 137-144Crossref PubMed Scopus (499) Google Scholar) revealed the presence of multiple N-terminal htt fragments smaller than the first 508 amino acids in the nucleus (18Zhou H. Cao F. Wang Z. Yu Z.X. Nguyen H.P. Evans J. Li S.H. Li X.J. J. Cell Biol. 2003; 163: 109-118Crossref PubMed Scopus (133) Google Scholar), conistent with the notion that cleavage of mutant htt is a key event in HD pathology (19Graham R.K. Deng Y. Slow E.J. Haigh B. Bissada N. Lu G. Pearson J. Shehadeh J. Bertram L. Murphy Z. Warby S.C. Doty C.N. Roy S. Wellington C.L. Leavitt B.R. Raymond L.A. Nicholson D.W. Hayden M.R. Cell. 2006; 125: 1179-1191Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar, 20Ellerby L.M. Orr H.T. Nature. 2006; 442: 641-642Crossref PubMed Scopus (12) Google Scholar). Because htt protein length can influence its cellular toxicity and ability to cause neurodegeneration in HD cellular models and transgenic mice (21Hackam A.S. Singaraja R. Wellington C.L. Metzler M. McCutcheon K. Zhang T. Kalchman M. Hayden M.R. J. Cell Biol. 1998; 141: 1097-1105Crossref PubMed Scopus (288) Google Scholar, 22Yu Z.X. Li S.H. Evans J. Pillarisetti A. Li H. Li X.J. J. Neurosci. 2003; 23: 2193-2202Crossref PubMed Google Scholar), it is important to know whether nuclear N-terminal htt fragments of different length can differentially affect gene transcription. Understanding this issue will help elucidate the mechanisms underlying the context-dependent neuropathology observed in various HD mouse models. In this study, we examined the interaction between mutant htt and the transcription factor Sp1. We demonstrate that this interaction is affected by htt protein context and further show that the ability of different N-terminal htt fragments to affect the activity of an Sp1-dependent promoter is context-dependent. In each case, shorter htt fragments, which are more likely to become misfolded, produced the greater inhibitory effect. The ability of these htt fragments to bind Sp1 and to reduce its activity was decreased by Hsp40 expression, suggesting that protein misfolding plays a key in this htt amino different in the in S.H. Lam S. Cheng A.L. Li X.J. Hum. Mol. Genet. 2000; PubMed Scopus Google Scholar). The repeat by A. A. C. 2001; PubMed Scopus Google Scholar) was into htt J. Cao F. Wang Ross C.A. Bates G.P. Li S.H. Li X.J. Genet. 2005; PubMed Scopus Google Scholar) to N-terminal mutant htt amino with an poly(Q) and The of the was to the of these htt to and The nerve growth factor promoter from the S. Rigamonti D. Valenza M. Zuccato C. Conti L. Pritchard J. Kooperberg C. Olson J.M. Cattaneo E. Hum. Mol. Genet. 2002; 11: 1953-1965Crossref PubMed Google Scholar) was into the multiple site of to the human Hsp40 in the which a was in H. Li S.H. Li X.J. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). and mouse to htt the first amino acids of human htt as (18Zhou H. Cao F. Wang Z. Yu Z.X. Nguyen H.P. Evans J. Li S.H. Li X.J. J. Cell Biol. 2003; 163: 109-118Crossref PubMed Scopus (133) Google Scholar, C.A. Li S.H. H. S. R. D. Hersch S.M. Li X.J. J. Neurosci. 1999; 19: PubMed Google Scholar). a mouse to poly(Q), was from Sp1 we used to Sp1 and to the Cell was used to Cell and embryonic kidney in with and and of which from mouse in with and in a into and for the for and as by of red fluorescent protein. of endogenous Sp1 from in a with htt for The and in of a for The 500 for The was with a for and for The was to with of as the for Sp1 of was to the and for The for and in The by and by with and of Sp1 from HD mouse we used S.W. M. M. Ross C.A. E. L. Bates G.P. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), G. M.W. K. J.A. Slunt H.H. T. Cooper J.K. Jenkins N.A. Copeland N.G. Ross C.A. Borchelt D.R. Hum. Mol. Genet. 1999; PubMed Google Scholar), and HD repeat knock-in (17Lin C.H. Tallaksen-Greene S. Chien W.M. Cearley J.A. Jackson W.S. Crouse A.B. Ren S. Li X.J. Albin R.L. Detloff P.J. Hum. Mol. Genet. 2001; 10: 137-144Crossref PubMed Scopus (499) Google Scholar) These mice the as (18Zhou H. Cao F. Wang Z. Yu Z.X. Nguyen H.P. Evans J. Li S.H. Li X.J. J. Cell Biol. 2003; 163: 109-118Crossref PubMed Scopus (133) Google Scholar, 22Yu Z.X. Li S.H. Evans J. Pillarisetti A. Li H. Li X.J. J. Neurosci. 2003; 23: 2193-2202Crossref PubMed Google Scholar). from brain of HD mice was as brain was in The was for was and in for The of was to with as by and by with and of was as (12Li S.H. Cheng A.L. Zhou H. Lam S. Rao M. Li H. Li X.J. Mol. Cell. Biol. 2002; 22: 1277-1287Crossref PubMed Scopus (284) Google Scholar). in and with of for the of the with in for with in and for and with primary in with with PBS, the with with in and for the of the for each with fluorescent and a used to with different The and was to and for with in in and with primary in and in PBS, for with in PBS, and in the of different fragments of htt the we in a for with and for from the and in of of the cell and of was in into a fluorescent with a and results are as of analysis was analysis of by multiple more was to be analysis of with was to the of htt. and of N-terminal whether protein length can the ability of htt to affect gene we used N-terminal htt htt htt amino acids with a These the of N-terminal htt fragments that can accumulate in the nucleus in from HD repeat knock-in mice (18Zhou H. Cao F. Wang Z. Yu Z.X. Nguyen H.P. Evans J. Li S.H. Li X.J. J. Cell Biol. 2003; 163: 109-118Crossref PubMed Scopus (133) Google Scholar). Because to the localization of the of htt in we the to the of each htt to its nuclear localization In this in the effects of the N-terminal htt fragments and in the nucleus are likely due to their protein analysis of htt revealed the molecular and of these htt fragments and nuclear localization of each htt was by Sp1 with N-terminal fragments in and in has been to with the transcriptional and this interaction is by poly(Q) expansion (12Li S.H. Cheng A.L. Zhou H. Lam S. Rao M. Li H. Li X.J. Mol. Cell. Biol. 2002; 22: 1277-1287Crossref PubMed Scopus (284) Google Scholar, 14Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (588) Google Scholar). the of htt protein length its binding to Sp1 has not been We used to the interactions of different htt fragments with Sp1 in We have found that htt can be with not Sp1 (12Li S.H. Cheng A.L. Zhou H. Lam S. Rao M. Li H. Li X.J. Mol. Cell. Biol. 2002; 22: 1277-1287Crossref PubMed Scopus (284) Google Scholar, J. Cao F. Wang Ross C.A. Bates G.P. Li S.H. Li X.J. Genet. 2005; PubMed Scopus Google Scholar). we the interaction of mutant htt with Sp1. We with endogenous and examined the by with and the levels of these htt fragments are a greater of shorter N-terminal fragments of htt with Sp1 than fragments. the N-terminal htt fragments the Sp1 the Although that in the the form of this protein was with Sp1. is with (12Li S.H. Cheng A.L. Zhou H. Lam S. Rao M. Li H. Li X.J. Mol. Cell. Biol. 2002; 22: 1277-1287Crossref PubMed Scopus (284) Google Scholar, 14Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (588) Google Scholar, Z.X. Li S.H. Nguyen H.P. Li X.J. Hum. Mol. Genet. 2002; 11: PubMed Scopus Google Scholar) that not mutant htt with Sp1. protein context the ability of htt to with Sp1. the context-dependent interaction of N-terminal htt with Sp1 in in HD mouse we examined different HD mouse models that express N-terminal full-length mutant htt. In brain from mice that express human htt amino with a repeat S.W. M. M. Ross C.A. E. L. Bates G.P. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), and htt in nuclear was and may a of htt. of htt with Sp1 htt not We examined HD transgenic mice that express the first amino acids of human htt with an repeat G. M.W. K. J.A. Slunt H.H. T. Cooper J.K. Jenkins N.A. Copeland N.G. Ross C.A. Borchelt D.R. Hum. Mol. Genet. 1999; PubMed Google Scholar). The transgenic htt was with Sp1 It is to the of htt from and transgenic mice of different we HD knock-in mice that express full-length htt with from the endogenous mouse (17Lin C.H. Tallaksen-Greene S. Chien W.M. Cearley J.A. Jackson W.S. Crouse A.B. Ren S. Li X.J. Albin R.L. Detloff P.J. Hum. Mol. Genet. 2001; 10: 137-144Crossref PubMed Scopus (499) Google Scholar) and can accumulate N-terminal htt fragments over time (18Zhou H. Cao F. Wang Z. Yu Z.X. Nguyen H.P. Evans J. Li S.H. Li X.J. J. Cell Biol. 2003; 163: 109-118Crossref PubMed Scopus (133) Google Scholar). We used the from the of HD knock-in mice of and with as it can N-terminal fragments of mutant htt in HD knock-in mouse nuclear and full-length htt as well as N-terminal htt fragments, to whether full-length N-terminal htt with transcription factors in the We endogenous Sp1 and examined the by with N-terminal htt fragments are not as as full-length htt in the for are become of full-length mutant htt. N-terminal htt fragments are with Sp1 as with full-length htt. Sp1 binding to N-terminal htt fragments, not full-length htt, with Because HD repeat knock-in mice show (17Lin C.H. Tallaksen-Greene S. Chien W.M. Cearley J.A. Jackson W.S. Crouse A.B. Ren S. Li X.J. Albin R.L. Detloff P.J. Hum. Mol. Genet. 2001; 10: 137-144Crossref PubMed Scopus (499) Google Scholar), the in the of Sp1 with N-terminal htt fragments is likely to contribute to transcriptional dysregulation and in this HD mouse N-terminal to Sp1 to whether the context-dependent interactions of htt with Sp1 are to in gene Sp1-dependent the promoter and and is The activity of the promoter is dependent Sp1 H. P.J. PubMed Scopus Google Scholar) and by mutant htt S.H. Cheng A.L. Li H. Li X.J. J. Neurosci. 1999; 19: 5159-5172Crossref PubMed Google Scholar, S.H. Cheng A.L. Zhou H. Lam S. Rao M. Li H. Li X.J. Mol. Cell. Biol. 2002; 22: 1277-1287Crossref PubMed Scopus (284) Google Scholar). we used the promoter as a to the of different htt fragments transcription. we used the promoter to a that red can be used to the activity of the promoter We with and Sp1 of Sp1 as with the that this activity is dependent we examined mouse D. G. Zhang F. A. S. J.M. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In the of was to was in mouse in which the normal Sp1 is the is a to Sp1-dependent gene transcription. we with and to htt protein length is important for its ability to affect Sp1 activity. htt decreased the inhibitory Because that the htt fragments levels these results the that the protein context of htt the ability of N-terminal htt fragments to gene for the of N-terminal for the of shorter N-terminal htt fragments Sp1 activity is that protein misfolding plays a in this htt fragments are more likely to become (21Hackam A.S. Singaraja R. Wellington C.L. Metzler M. McCutcheon K. Zhang T. Kalchman M. Hayden M.R. J. Cell Biol. 1998; 141: 1097-1105Crossref PubMed Scopus (288) Google Scholar, C.A. Li S.H. H. S. R. D. Hersch S.M. Li X.J. J. Neurosci. 1999; 19: PubMed Google Scholar) as by the between protein length and for and In the protein is by molecular whereas of is by the A. P. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, F.U. Hayer-Hartl M. Science. 2002; PubMed Scopus Google Scholar, Genet. 2003; 13: PubMed Scopus Google Scholar). It is likely that the nuclear is more for mutant htt to become misfolded, as chaperone B. A.W. K. H.H. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) and (18Zhou H. Cao F. Wang Z. Yu Z.X. Nguyen H.P. Evans J. Li S.H. Li X.J. J. Cell Biol. 2003; 163: 109-118Crossref PubMed Scopus (133) Google Scholar) have been to be in the nucleus than the this we htt of its to and We with htt a repeat and htt by The first and htt C.A. Li S.H. H. S. R. D. Hersch S.M. Li X.J. J. Neurosci. 1999; 19: PubMed Google Scholar), whereas the is specific to poly(Q) and not of mutant htt (18Zhou H. Cao F. Wang Z. Yu Z.X. Nguyen H.P. Evans J. Li S.H. Li X.J. J. Cell Biol. 2003; 163: 109-118Crossref PubMed Scopus (133) Google Scholar, A. L. C. Devys D. J.L. Y. Mol. Cell. 2002; 10: Full Text Full Text PDF PubMed Scopus Google Scholar). and to the that by not it has a shorter poly(Q) mutant htt in the nucleus, we used for was in the nucleus, and its nuclear localization was revealed by not mutant htt in the nucleus, it was to mutant htt in the We have that with mutant htt and Hsp40 express and that Hsp40 can reduce poly(Q) H. Li S.H. Li X.J. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). in the with and Hsp40, the htt the nuclear of mutant htt by Because show of mutant htt in the nucleus and H. Cao F. Wang Z. Yu Z.X. Nguyen H.P. Evans J. Li S.H. Li X.J. J. Cell Biol. 2003; 163: 109-118Crossref PubMed Scopus (133) Google Scholar), these results the that mutant htt in the nucleus a that in misfolding of nuclear htt to its factors that reduce htt misfolding its ability to with Sp1 and Sp1 activity. this we used the molecular chaperone Hsp40, which can htt misfolding and J. Cao F. Wang Ross C.A. Bates G.P. Li S.H. Li X.J. Genet. 2005; PubMed Scopus Google Scholar, H. Li S.H. Li X.J. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the of and in htt by Hsp40 Hsp40 decreased the of htt with Sp1 We examined the of Hsp40 the activity of in with the htt mutant htt the transcriptional activity of the Hsp40 reversed this In the of Hsp40 the promoter as with suggesting that Hsp40 reduces mutant Sp1-dependent gene transcription. htt misfolding is important for its ability to with Sp1 and reduce Sp1 activity specific that htt misfolding can normal Sp1 function. In the study, we show that Sp1 interacts with multiple N-terminal fragments of htt in the nucleus in and HD mouse these interactions are by htt protein htt fragments more Sp1 than fragments and the transcriptional activity from the which is to be by Sp1 H. P.J. PubMed Scopus Google Scholar). with that htt length reduces the number of gene in HD mice R. Strand A. S.M. Hanson S.A. M.M. Kooperberg C. Chase K.O. M. Young A.B. Leavitt B.R. Cha J.H. Aronin N. Hayden M.R. Olson J.M. Hum. Mol. Genet. 2002; 11: PubMed Scopus Google Scholar), analysis of Sp1 and its transcriptional activity in that smaller N-terminal htt fragments may have a transcriptional activity than htt fragments. The context-dependent of mutant htt transcription factors may contribute to different in HD mice different of mutant htt. htt misfolding to its ability to bind Sp1 and reduce Sp1-dependent activity of the promoter and Hsp40, which htt this further insight into the effects of molecular chaperones in HD H. Breuer P. Hayer-Hartl Hartl F.U. S. A. 2002; Scopus Google Scholar). In of this chaperones are found to reduce the interaction of mutant htt with protein G. Breuer P. Boteva R. Behrends C. Tzvetkov N. Strippel N. Sakahira H. Siegers K. Hayer-Hartl M. Hartl F.U. Mol. Cell. 2004; 15: 95-105Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar). The in the suggest a in which htt fragments, the nucleus, a with and Sp1 in gene In HD repeat knock-in mice that show an in of mutant N-terminal htt fragments and their of nuclear (17Lin C.H. Tallaksen-Greene S. Chien W.M. Cearley J.A. Jackson W.S. Crouse A.B. Ren S. Li X.J. Albin R.L. Detloff P.J. Hum. Mol. Genet. 2001; 10: 137-144Crossref PubMed Scopus (499) Google Scholar, H. Cao F. Wang Z. Yu Z.X. Nguyen H.P. Evans J. Li S.H. Li X.J. J. Cell Biol. 2003; 163: 109-118Crossref PubMed Scopus (133) Google Scholar), the of N-terminal fragments of mutant htt with Sp1 in the brain is with of the of genes has been to become more severe over time in HD mouse models R. Strand A. S.M. A.S. A.S. Schilling G. Ross C.A. Borchelt D.R. Young A.B. Cha J.H. Olson J.M. Hum. Mol. Genet. 2000; PubMed Scopus Google Scholar). Because mutant htt shorter htt fragments may bind Sp1 and Sp1 binding to promoter DNA form It be that Sp1 the of a number of genes and is to be in models of HD A.S. Sadri-Vakili G. Yohrling G.J. Braveman M.W. Benn C.L. Glajch K.E. Dirocco D.P. Farrell L.A. Krainc D. Gines S. Macdonald M.E. Cha J.H. Neurobiol. Dis. 2006; 22: 233-241Crossref PubMed Scopus (89) Google Scholar, Z. F. R. B. V. R. B. Benn C.L. Dirocco D. Cha J.H. Hersch S.M. J. Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). It is that Sp1 is by in H. J. K. J. Ross R. J. Neurosci. 2003; 23: PubMed Google Scholar). Mutant htt causes to Sp1 which may genes that can cellular certain has that mutant htt the binding of Sp1 to DNA and suppresses the transcription of certain genes (12Li S.H. Cheng A.L. Zhou H. Lam S. Rao M. Li H. Li X.J. Mol. Cell. Biol. 2002; 22: 1277-1287Crossref PubMed Scopus (284) Google Scholar, 13Chen-Plotkin A.S. Sadri-Vakili G. Yohrling G.J. Braveman M.W. Benn C.L. Glajch K.E. Dirocco D.P. Farrell L.A. Krainc D. Gines S. Macdonald M.E. Cha J.H. Neurobiol. Dis. 2006; 22: 233-241Crossref PubMed Scopus (89) Google Scholar, 14Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (588) Google Scholar, 15Zhai W. Jeong H. Cui L. Krainc D. Tjian R. Cell. 2005; 123: 1241-1253Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). Our further demonstrate that this inhibitory is context-dependent. Because mutant htt interacts with multiple transcription factors (6Li S.H. Li X.J. Trends Genet. 2004; 20: 146-154Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar), it is that these interactions are context-dependent and that protein context and are key of of transcription factors by mutant htt. context-dependent of transcription contribute to the specific neuropathology in We for and cell