Abstract
Transcriptional dysregulation has emerged as a central pathogenic mechanism in Huntington's disease (HD), which is associated with neuropathological changes predominantly in the striatum. Here we demonstrate that expression of Bcl11b (a.k.a. CTIP2), a transcription factor exhibiting highly-enriched localization in adult striatum, is significantly decreased in HD cells, mouse models and human subjects and that overexpression of Bcl11b attenuates toxic effects of mutant huntingtin in cultured striatal neurons. We show that Bcl11b directly activates the proximal promoter regions of striatal-enriched genes and can increase mRNA levels of striatal-expressing genes. We further demonstrate an interaction between Bcl11b and huntingtin protein in cultured cells and brain homogenates from HD R6/1 and YAC72 transgenic mice. We propose that sequestration and/or decreased expression of Bcl11b in HD is responsible, at least in part, for the dysregulation of striatal gene expression observed in HD and may contribute to the specificity of pathology observed in this disease.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Binding Sites / genetics
-
Cell Differentiation / genetics
-
Cell Line, Transformed
-
Corpus Striatum / metabolism*
-
Corpus Striatum / physiopathology
-
DNA-Binding Proteins / genetics*
-
DNA-Binding Proteins / metabolism
-
Down-Regulation / genetics
-
Female
-
Gene Expression Regulation / genetics*
-
Humans
-
Huntingtin Protein
-
Huntington Disease / genetics*
-
Huntington Disease / metabolism*
-
Huntington Disease / physiopathology
-
Male
-
Mice
-
Mice, Transgenic
-
Middle Aged
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / metabolism
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism
-
Phenotype
-
Promoter Regions, Genetic / genetics
-
RNA, Messenger / metabolism
-
Repressor Proteins / genetics*
-
Repressor Proteins / metabolism
-
Transcription Factors / genetics
-
Transcription, Genetic / genetics*
-
Transcriptional Activation / genetics
-
Tumor Suppressor Proteins / genetics*
-
Tumor Suppressor Proteins / metabolism
Substances
-
BCL11B protein, human
-
DNA-Binding Proteins
-
HTT protein, human
-
Huntingtin Protein
-
Nerve Tissue Proteins
-
Nuclear Proteins
-
RNA, Messenger
-
Repressor Proteins
-
Transcription Factors
-
Tumor Suppressor Proteins