The transcriptional repressor, REST (RE1 Silencing Transcription Factor;also called NRSF), was discovered in 1995 as a regulator or the gene encoding the voltage-dependent sodium channel, a protein crucial for the propagation of action potentials in most nervous systems. In the last funding period, by developing new reagents and techniques, we showed that REST control extends much farther than select excitability proteins;it regulates a large suite of genes that together define the neuronal phenotype. Many of these genes encode signature proteins of neuroendocrine tumors and may be involved in other types of epithelial cancers as well. We also found that REST controls a family of microRNAs that promote the neuronal phenotype in unexpected ways. Finally, we showed that, by orchestrating different chromatin and DNA modifications, REST plays important roles in controlling neuronal gene expression in pluripotent embryonic stem cells, neural stem/progenitors, and terminally differentiated cells. In the next grant period, we will 1) use a novel purification method to test two models by which REST recruits different chromatin complexes in different cellular contexts, 2) exploit a new mouse line we have generated to test whether REST plays major roles in neural stem/progenitors in adult neurogenesis as it does during embryogenesis, and 3) use a new method we have developed to elucidate comprehensive target mRNAs of miRNAs to understand how combinations of miRNAs function to promote the neuronal phenotype. Our studies will contribute insights into fundamental questions of gene regulation, as well as mechanisms that distinguish pluripotent from terminally differentiated phenotypes, an issue of obvious importance to understanding the origins of neural tumorigenesis.

Public Health Relevance

REST continues to sit at the cutting edge of our understanding of fundamental cellular processes as well as neurogenesis. In the last funding period, in collaboration with the Elledge lab (HMS), we showed that certain human epithelial cancers are due to mis-expression of neuronal genes, linked likely to the dysregulation of REST. Our proposed studies represent several different attacks on the fundamental question of how control of neuronal gene chromatin is linked to formation of neural tumors, through studies of REST in different cellular contexts, from pluripotent embryonic stem cells, to neural stem/progenitors, to terminally differentiated non-neuronal cells.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Mamounas, Laura
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Oregon Health and Science University
Schools of Medicine
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Yao, Huilan; Goldman, Devorah C; Nechiporuk, Tamilla et al. (2014) Corepressor Rcor1 is essential for murine erythropoiesis. Blood 123:3175-84
McGann, James C; Oyer, Jon A; Garg, Saurabh et al. (2014) Polycomb- and REST-associated histone deacetylases are independent pathways toward a mature neuronal phenotype. Elife 3:e04235
Gu, Haidong; Liang, Yu; Mandel, Gail et al. (2005) Components of the REST/CoREST/histone deacetylase repressor complex are disrupted, modified, and translocated in HSV-1-infected cells. Proc Natl Acad Sci U S A 102:7571-6
Roizman, Bernard; Gu, Haidong; Mandel, Gail (2005) The first 30 minutes in the life of a virus: unREST in the nucleus. Cell Cycle 4:1019-21
Dallman, Julia E; Allopenna, Janet; Bassett, Andrew et al. (2004) A conserved role but different partners for the transcriptional corepressor CoREST in fly and mammalian nervous system formation. J Neurosci 24:7186-93
Battaglioli, Elena; Andres, Maria E; Rose, Dave W et al. (2002) REST repression of neuronal genes requires components of the hSWI.SNF complex. J Biol Chem 277:41038-45
Hakimi, Mohamed-Ali; Bochar, Daniel A; Chenoweth, Josh et al. (2002) A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc Natl Acad Sci U S A 99:7420-5
Ballas, N; Battaglioli, E; Atouf, F et al. (2001) Regulation of neuronal traits by a novel transcriptional complex. Neuron 31:353-65
Boiko, T; Rasband, M N; Levinson, S R et al. (2001) Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 30:91-104
Grimes, J A; Nielsen, S J; Battaglioli, E et al. (2000) The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex. J Biol Chem 275:9461-7

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