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 l…
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Consequently, REST translocates to the nucleus, occupies RE1 repressor sequences, and decreases neuronal gene expression.
“Consequently, REST translocates to the nucleus, occupies RE1 repressor sequences and decreases neuronal gene expression.”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Zuccato et al., 2003
In neurons, REST is sequestered in the cytoplasm in part through binding to huntingtin.
“In neurons, the protein is sequestered in the cytoplasm in part through binding to huntingtin.”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Zuccato et al., 2003
REST silences neuronal gene expression in non-neuronal cells.
“The transcription factor REST silences neuronal gene expression in non-neuronal cells.”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Zuccato et al., 2003
In patients with Huntington's disease, mutant Huntingtin fails to bind REST, enabling its nuclear translocation.
“However, in patients with HD mutant Htt fails to bind REST enabling its nuclear translocation (Zuccato et al., 2003).”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Zuccato et al., 2003
In mature, healthy neurons, REST is expressed at low levels and primarily sequestered in the cytoplasm in part through interaction with Huntingtin.
“In mature, healthy neurons, REST is expressed at low levels and primarily sequestered in the cytoplasm in part through interaction with Htt (Zuccato et al., 2003).”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Zuccato et al., 2003
One putative mechanism underlying the transcriptional changes in Huntington's disease is aberrant cellular distribution of the transcriptional repressor REST.
“One putative mechanism underlying the transcriptional changes is aberrant cellular distribution of the transcriptional repressor RE1-silencing transcription factor (REST, also known as neuronal restrictive silencing factor, NRSF) (Lunyak et al., 2002; Zuccato et al., 2003 ; Zuccato et al., 2007).”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Zuccato et al., 2003
Once in the nucleus, REST can bind RE1 consensus sequences and recruit co-repressors including mSin3, CoREST, and MeCP2 to inactivate neuron-specific genes.
“Once in the nucleus, REST can bind RE1 consensus sequences and recruit co-repressors including mSin3, the co-repressor of REST (CoREST, also known as RCOR1) and methyl CpG binding protein 2 (MeCP2) (Andres et al., 1999) to inactivate neuron-specific genes (Zuccato et al., 2003; Conaco et al., 2006).”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Zuccato et al., 2003
Polyglutamine expansions in huntingtin, which causes Huntington's disease, abrogate REST-huntingtin binding.
“Polyglutamine expansions in huntingtin, which causes Huntington’s disease (HD), abrogates REST-huntingtin binding.”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Zuccato et al., 2003
REST is mislocalized in brains of patients with Huntington's disease, with increased nuclear localization and occupancy at RE1 sites compared to healthy controls.
“The transcriptional repressor REST is mislocalized in brains of patients with HD, with increased nuclear localization and occupancy at RE1 sites compared to healthy controls (Zuccato et al., 2003 ; Zuccato et al., 2007).”
From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Zuccato et al., 2003
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- Authors
- Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, B. R., Hayden, M. R., Timmusk, T., Rigamonti, D., & Cattaneo, E.
- Venue
- Nature Genetics
- Published
- 2003-07-27
- Volume
- 35
- Issue
- 1
- Pages
- 76-83
- ISSN
- 1061-4036
- 1546-1718
- Cited by
- 814
- References
- 3
- Language
- en
- Licence
- www.springer.com/tdm (tdm)
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