Brain-specific factors in combination with mutant huntingtin induce gene-specific transcriptional dysregulation.
Mutant huntingtin lowered steady-state levels of DARPP-32 mRNA in the brain but not kidney of R6 transgenic HD mice by repressing transcription from one of two promoters. The activity of DARPP-32 promoter deletion constructs were lower in the presence of mutant huntingtin in immortalized striatal cell lines but no difference in transcription factor binding to the promoter was detected. The activity of CMV, TK and HPRT promoters was also affected by mutant huntingtin in these cell lines. Transient transfection experiments demonstrated that short-term expression of mutant huntingtin exerted a cell- and promoter-specific transcriptional repression. In in vitro experiments, transcription of the CMV promoter was reduced in the presence of striatal proteins and mutant huntingtin. It is likely that select combinations of trans-acting factors, co-activators and components of the Pol II holoenzyme acting in concert provide the basis for both the gene- and tissue-specific effects of mutant huntingtin.
Gomez
Geraldine T
GT
Department of Pharmacology, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5.
Hu
Haibei
H
McCaw
Elizabeth A
EA
Denovan-Wright
Eileen M
EM
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D017403:In Situ Hybridization; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D013937:Thymidine Kinase / Q000235:genetics; D014158:Transcription, Genetic
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C497929:Ppp1r1b protein, mouse; D007041:Hypoxanthine Phosphoribosyltransferase; D013937:Thymidine Kinase