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J. Biol. Chem., Vol. 282, Issue 41, 30039-30050, October 12, 2007

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Synergy between the RE-1 Silencer of Transcription and NFB in the Repression of the Neurotransmitter Gene TAC1 in Human Mesenchymal Stem Cells^*

Steven J. Greco¹, Sergey V. Smirnov, Raghav G. Murthy, and Pranela Rameshwar²

From the Department of Medicine, Division of Hematology/Oncology, and the Department of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103

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-1. We thus compared the effects of interleukin-1 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 NFB 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 NFB in the suppression of TAC1 in non-neuronal cells.

Received for publication, April 10, 2007 , and in revised form, August 16, 2007.

^* This work was supported by a grant from the F. M. Kirby Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Performed this work in partial fulfillment of a Ph.D. thesis.

² To whom correspondence address should be addressed: UMDNJ-NJMS, MSB, Rm. E-579, 185 South Orange Ave., Newark, NJ 07103. Tel.: 973-972-0625; Fax: 973-972-8854; E-mail: rameshwa{at}umdnj.edu.

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