Brain-specific factors in combination with mutant huntingtin induce gene-specific transcriptional dysregulation

Abstract

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.