Synergy between the RE-1 silencer of transcription and NFκB in the repression of the neurotransmitter gene TAC1 in human mesenchymal stem cells

Steven J. Greco, Sergey V. Smirnov, Raghav G. Murthy, Pranela Rameshwar

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

The RE-1 silencer of transcription (REST) is a transcriptional regulator that represses neuron-specific genes in non-neuronal tissues by remodeling chromatin structure. We have utilized human mesenchymal stem cells (MSCs) as a research tool to understand the molecular mechanisms that regulate a neurogenic program of differentiation in non-neuronal tissue. MSCs are mesoderm-derived cells that generate specialized cells such as stroma, fat, bone, and cartilage. We have reported previously the transdifferentiation of MSCs into functional neuronal cells (Cho, K. J., Trzaska, K. A., Greco, S. J., McArdle, J., Wang, F. S., Ye, J.-H., and Rameshwar, P. (2005) Stem Cells 23, 383-391). Expression of the neurotransmitter gene TAC1 was detected only in neuronal cells and thus served as a model to study transcriptional regulation of neuron-specific genes in undifferentiated MSCs. Bone marrow stromal cells are known to transiently express TAC1 following stimulation with the microenvironmental factor interleukin-1α. We thus compared the effects of interleukin-1α stimulation and neuronal induction of MSCs on TAC1 regulation. Transcription factor mapping of the 5′-flanking region of the TAC1 promoter predicted two REST-binding sites adjacent to one NFκB site within exon 1. Chromatin immunoprecipitation, mutagenesis, and loss-of-function studies showed that both transcription factors synergistically mediated repression of TAC1 in the neurogenic and microenvironmental models. Together, the results support the novel finding of synergism between REST and NFκB in the suppression of TAC1 in non-neuronal cells.

Original languageEnglish (US)
Pages (from-to)30039-30050
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number41
DOIs
StatePublished - Oct 12 2007

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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