Abstract
BackgroundThe 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.Methodology/Principal FindingsIn this study, we utilized chromatin immunoprecipitation on chip (ChIP-chip) analysis to examine REST and CoREST functions during NSC-mediated specification of cholinergic neurons (CHOLNs), GABAergic neurons (GABANs), glutamatergic neurons (GLUTNs), and medium spiny projection neurons (MSNs). We identified largely distinct but overlapping profiles of REST and CoREST target genes during neuronal subtype specification including a disproportionately high percentage that are exclusive to each neuronal subtype.Conclusions/SignificanceOur findings demonstrate that the differential deployment of REST and CoREST is an important regulatory mechanism that mediates neuronal subtype specification by modulating specific gene networks responsible for inducing and maintaining neuronal subtype identity. Our observations also implicate a broad array of factors in the generation of neuronal diversity including but not limited to those that mediate homeostasis, cell cycle dynamics, cell viability, stress responses and epigenetic regulation.
Highlights
The repressor element-1 silencing transcription factor/neuronrestrictive silencer factor (REST/NRSF) is a transcriptional regulator with genome-wide effects important for orchestrating neuronal development [1]
glutamatergic neurons (GLUTNs) derived from radial glia (RG) cells [23,24] acquired expression of the early neuronal linage marker, b tubulin III and exhibited complete overlap with the excitatory neurotransmitter, glutamate, while ventral forebrain derived neuronal species were identified by their co-expression of b tubulin III in concert with acquisition of distinct neurotransmitters (GABA for GABAergic neurons (GABANs)) or substrates and enzymes required for the processing and synthesis of neuronal subtype specific neurotransmitters (DARPP32, medium spiny projection neurons (MSNs) and ChAT, cholinergic neurons (CHOLNs), respectively) [25] (Figure S1)
By characterizing corresponding profiles of genome-wide REST and corepressor for element-1-silencing transcription factor (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
Summary
The repressor element-1 silencing transcription factor/neuronrestrictive silencer factor (REST/NRSF) is a transcriptional regulator with genome-wide effects important for orchestrating neuronal development [1]. The differential roles played by REST depend on its ability to recruit a series of epigenetic and regulatory cofactors to its N- and Cterminal domains These highly plastic macromolecular complexes often include another important transcriptional regulator, the corepressor for element-1-silencing transcription factor (CoREST), the primary cofactor of REST [7]. 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
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