Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes

Abstract

Huntingtin protein is mutated in Huntington disease. We previously reported that wild-type but not mutant huntingtin stimulates transcription of the gene encoding brain-derived neurotrophic factor (BDNF; ref. 2). Here we show that the neuron restrictive silencer element (NRSE) is the target of wild-type huntingtin activity on BDNF promoter II. Wild-type huntingtin inhibits the silencing activity of NRSE, increasing transcription of BDNF. We show that this effect occurs through cytoplasmic sequestering of repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF), the transcription factor that binds to NRSE. In contrast, aberrant accumulation of REST/NRSF in the nucleus is present in Huntington disease. We show that wild-type huntingtin coimmunoprecipitates with REST/NRSF and that less immunoprecipitated material is found in brain tissue with Huntington disease. We also report that wild-type huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype. Consistently, loss of expression of NRSE-controlled neuronal genes is shown in cells, mice and human brain with Huntington disease. We conclude that wild-type huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. These data identify a new mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes.

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

“…Huntington's disease is caused by a trinucleotide expansion that leads to the formation of inclusions and subsequent neurodegeneration in the striatum and cortex. The product of the Huntington's disease gene, huntingtin, interacts with the transcriptional factor RE1-silencing transcription factor (REST) [85][86][87]. REST recruits histone deacetylases (HDAC) to promoters [87] and induces changes in the expression of neuronal miRNAs (miR-124, miR-134, miR-29a, miR-29b, miR-9/9*, miR-132 and miR-330-3p) [84,85,88].…”

REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis

“…18,[29][30][31][32][33][34][35][36][37][38][39][40] Recently, mutations in REST have been shown to predispose to Wilms tumor (MIM: 616806). 41 The identified REST mutations in individuals with Wilms tumor were clustered within the zinc-finger DNA-binding domain of REST ( Figure 2C).…”

Epigenetic regulation of oxysterol formation

“…Epigentic mechanisms can contribute to the explanation for these phenomenon -the huntingtin protein is known to sequester the REST protein in the cytoplasm, preventing it from entering the nucleus where it normally plays a role in suppressing many genes [59]. Preliminary evidence indicates that CYP46A1 is one such gene as transfection with dnREST increases the expression and there are candidate REST binding sites in CYP46A1.…”