Regulation of RE1 Protein Silencing Transcription Factor (REST) Expression by HIP1 Protein Interactor (HIPPI)

Moumita Datta,Nitai P Bhattacharyya

doi:10.1074/jbc.m111.265173

Moumita Datta, Nitai P Bhattacharyya

Open Access

https://doi.org/10.1074/jbc.m111.265173

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Abstract

Earlier we have shown that the proapoptotic protein HIPPI (huntingtin interacting protein 1 (HIP1) protein interactor) along with its molecular partner HIP1 could regulate transcription of the caspase-1 gene. Here we report that RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a new transcriptional target of HIPPI. HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). The ability of HIPPI to activate REST gene transcription was dependent on HIP1, the nuclear transporter of HIPPI. Using a Huntington disease cell model, we have demonstrated that feeble interaction of HIP1 with mutant huntingtin protein resulted in increased nuclear accumulation of HIPPI and HIP1, leading to higher occupancy of HIPPI at the REST promoter, triggering its transcriptional activation and consequent repression of REST target genes. This novel transcription regulatory mechanism of REST by HIPPI may contribute to the deregulation of transcription observed in the cell model of Huntington disease.

Highlights

HIPPI, along with its molecular partner HIP1, can regulate transcription of the caspase-1 gene
Induction of REST Gene Transcription by HIPPI in HeLa Cells— From microarray experiments, we observed that exogenous expression of HIPPI increased REST expression together with that of many other genes in HeLa cells
To address the functional consequence of such HIPPI-mediated up-regulation of the REST gene in HeLa cells, we measured the expression level of PENK, a gene negatively regulated by REST [15]

Summary

Background

HIPPI, along with its molecular partner HIP1, can regulate transcription of the caspase-1 gene. Using a Huntington disease cell model, we have demonstrated that feeble interaction of HIP1 with mutant huntingtin protein resulted in increased nuclear accumulation of HIPPI and HIP1, leading to higher occupancy of HIPPI at the REST promoter, triggering its transcriptional activation and consequent repression of REST target genes. This novel transcription regulatory mechanism of REST by HIPPI may contribute to the deregulation of transcription observed in the cell model of Huntington disease. We have demonstrated that occupancy of HIPPI in the REST promoter was higher in STHdhQ111/Q111 cells compared with STHdhQ7/Q7 cells, which led to increased expression of REST and a consequent up-regulation of REST-mediated neuronal gene repression in STHdhQ111/Q111 cells

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION