Transcriptional activation of REST by Sp1 in Huntington's disease models

PLoS One. 2010 Dec 14;5(12):e14311. doi: 10.1371/journal.pone.0014311.


In Huntington's disease (HD), mutant huntingtin (mHtt) disrupts the normal transcriptional program of disease neurons by altering the function of several gene expression regulators such as Sp1. REST (Repressor Element-1 Silencing Transcription Factor), a key regulator of neuronal differentiation, is also aberrantly activated in HD by a mechanism that remains unclear. Here, we show that the level of REST mRNA is increased in HD mice and in NG108 cells differentiated into neuronal-like cells and expressing a toxic mHtt fragment. Using luciferase reporter gene assay, we delimited the REST promoter regions essential for mHtt-mediated REST upregulation and found that they contain Sp factor binding sites. We provide evidence that Sp1 and Sp3 bind REST promoter and interplay to fine-tune REST transcription. In undifferentiated NG108 cells, Sp1 and Sp3 have antagonistic effect, Sp1 acting as an activator and Sp3 as a repressor. Upon neuronal differentiation, we show that the amount and ratio of Sp1/Sp3 proteins decline, as does REST expression, and that the transcriptional role of Sp3 shifts toward a weak activator. Therefore, our results provide new molecular information to the transcriptional regulation of REST during neuronal differentiation. Importantly, specific knockdown of Sp1 abolishes REST upregulation in NG108 neuronal-like cells expressing mHtt. Our data together with earlier reports suggest that mHtt triggers a pathogenic cascade involving Sp1 activation, which leads to REST upregulation and repression of neuronal genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Neurons / metabolism
  • Nuclear Proteins / genetics*
  • Promoter Regions, Genetic
  • Rats
  • Repressor Proteins / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Sp1 Transcription Factor / metabolism*
  • Transcriptional Activation*


  • Htt protein, rat
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RE1-silencing transcription factor
  • Repressor Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse
  • Sp1 Transcription Factor