Research Article: REST and CoREST Modulate Neuronal Subtype Specification, Maturation and Maintenance

Date Published: December 7, 2009

Publisher: Public Library of Science

Author(s): Joseph J. Abrajano, Irfan A. Qureshi, Solen Gokhan, Deyou Zheng, Aviv Bergman, Mark F. Mehler, Hitoshi Okazawa. http://doi.org/10.1371/journal.pone.0007936

Abstract: The repressor element-1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a master regulator of neuronal gene expression. REST functions as a modular scaffold for dynamic recruitment of epigenetic regulatory factors including its primary cofactor, the corepressor for element-1-silencing transcription factor (CoREST), to genomic loci that contain the repressor element-1 (RE1) binding motif. While REST was initially believed to silence RE1 containing neuronal genes in neural stem cells (NSCs) and non-neuronal cells, emerging evidence shows an increasingly complex cell type- and developmental stage-specific repertoire of REST target genes and functions that include regulation of neuronal lineage maturation and plasticity.

Partial Text: The repressor element-1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a transcriptional regulator with genome-wide effects important for orchestrating neuronal development [1]. REST binds to repressor element-1 (RE1) consensus motifs [2] which are primarily located in promoter regions of genes responsible for fundamental mature neuronal traits including: ion channels, adhesion molecules, synaptic vesicle proteins, growth factors and hormones, axonal guidance and vesicle trafficking, and neurotransmitter receptors [3], [4], [5]. While REST was initially believed to repress transcription of these neuronal genes in neural stem cells (NSCs) and in non-neuronal cells, recent evidence suggests a much broader role for REST, with context-specific and sometimes seemingly paradoxical functions in embryonic stem cells (ESCs), NSCs, mature neurons, and other cell types [3], [5], [6].

We examined the molecular mechanisms that underlie neuronal subtype specification by characterizing REST and CoREST protein expression and target gene profiles using ChIP-chip analysis in a developmental paradigm associated with the elaboration of mature neuronal subtypes. We identified REST and CoREST target genes that are unique to a specific neuronal subtype and also those found in multiple subtypes. In addition, we interrogated the potential roles of REST and CoREST in regulating gene expression during neuronal subtype specification by examining correlations between profiles of REST and CoREST promoter occupancy and corresponding target gene expression patterns during critical developmental transitions.

The developmental fates of stem and progenitor cells within the nervous system are determined by a complex series of spatial and temporal extracellular cues which induce selective classes of cross-repressive patterning genes and combinatorial transcription factor codes that ultimately lead to cellular functional diversification. We interrogated these molecular mechanisms and found that REST and CoREST appear to play key roles in orchestrating neuronal subtype specific gene expression programs. By characterizing corresponding profiles of genome-wide REST and CoREST promoter occupancy and gene expression in a number of terminally differentiated neuronal subtypes (e.g., CHOLNs, GABANs, GLUTNs, and MSNs), we identified neuronal subtype specific REST and CoREST “regulons” [4] which seem to be important for promoting features associated with a particular neuronal subtype while concurrently repressing characteristics of alternative neural cell types. These observations support the conclusion that the highly selective REST and CoREST regulons that we uncovered mediate neuronal subtype specification.

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http://doi.org/10.1371/journal.pone.0007936

 

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