Differential Deployment of REST and CoREST Promotes Glial Subtype Specification and Oligodendrocyte Lineage Maturation

Joseph J Abrajano,Deyou Zheng,Solen Gokhan,Aviv Bergman,Mark F Mehler,Irfan A Qureshi,Rafael Linden

doi:10.1371/journal.pone.0007665

Abstract

BackgroundThe repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a master transcriptional regulator that binds to numerous genomic RE1 sites where it acts as a molecular scaffold for dynamic recruitment of modulatory and epigenetic cofactors, including corepressor for element-1-silencing transcription factor (CoREST). CoREST also acts as a hub for various cofactors that play important roles in epigenetic remodeling and transcriptional regulation. While REST can recruit CoREST to its macromolecular complex, CoREST complexes also function at genomic sites independently of REST. REST and CoREST perform a broad array of context-specific functions, which include repression of neuronal differentiation genes in neural stem cells (NSCs) and other non-neuronal cells as well as promotion of neurogenesis. Despite their involvement in multiple aspects of neuronal development, REST and CoREST are not believed to have any direct modulatory roles in glial cell maturation.Methodology/Principal FindingsWe challenged this view by performing the first study of REST and CoREST in NSC-mediated glial lineage specification and differentiation. Utilizing ChIP on chip (ChIP-chip) assays, we identified distinct but overlapping developmental stage-specific profiles for REST and CoREST target genes during astrocyte (AS) and oligodendrocyte (OL) lineage specification and OL lineage maturation and myelination, including many genes not previously implicated in glial cell biology or linked to REST and CoREST regulation. Amongst these factors are those implicated in macroglial (AS and OL) cell identity, maturation, and maintenance, such as members of key developmental signaling pathways and combinatorial transcription factor codes.Conclusions/SignificanceOur results imply that REST and CoREST modulate not only neuronal but also glial lineage elaboration. These factors may therefore mediate critical developmental processes including the coupling of neurogenesis and gliogenesis and neuronal-glial interactions that underlie synaptic and neural network plasticity and homeostasis in health and in specific neurological disease states.

Highlights

The repressor element-1 silencing transcription factor/neuronrestrictive silencer factor (REST/NRSF) is a master transcriptional and post-transcriptional regulator [1] that modulates distinct sets of protein-coding and non-coding genes in specific cell types, such as embryonic stem cells (ESCs) and neural stem cells (NSCs) [2], and has a broad array of context-specific functions including the regulation of embryonic development [3], neurogenesis [4,5], synaptic plasticity [4], neurosecretory mechanisms [6], and extracellular matrix composition [7]
We identified profiles for REST and corepressor for element-1-silencing transcription factor (CoREST) target genes that are unique to specific cell types as well as those found in combinations throughout critical developmental transitions associated with glial lineage specification and progressive stages of OL lineage maturation
REST and CoREST Expression and Subcellular Localization We measured REST and CoREST expression and subcellular localization throughout glial lineage elaboration by performing immunofluorescence microscopy and Western blot analysis (Figure 1). We found that both proteins are ubiquitously expressed in the nucleus and cytoplasm of all cell types examined in our developmental paradigm. These observations suggest that REST and CoREST are present in all glial cell types and have the potential to regulate gene expression profiles during glial subtype specification and progressive stages of OL lineage maturation

Summary

Introduction

The repressor element-1 silencing transcription factor/neuronrestrictive silencer factor (REST/NRSF) is a master transcriptional and post-transcriptional regulator [1] that modulates distinct sets of protein-coding and non-coding genes in specific cell types, such as embryonic stem cells (ESCs) and neural stem cells (NSCs) [2], and has a broad array of context-specific functions including the regulation of embryonic development [3], neurogenesis [4,5], synaptic plasticity [4], neurosecretory mechanisms [6], and extracellular matrix composition [7]. REST was initially believed to repress expression of genomic repressor element-1 (RE1) motif containing neuronal differentiation genes in NSCs and in non-neuronal cells by recruiting chromatin remodeling enzymes and other regulatory cofactors to its N- and C-terminal binding domains, including the corepressor for element-1-silencing transcription factor (CoREST) to its Cterminus [11,12,13], to form a modular macromolecular complex. REST and CoREST perform a broad array of context-specific functions, which include repression of neuronal differentiation genes in neural stem cells (NSCs) and other non-neuronal cells as well as promotion of neurogenesis Despite their involvement in multiple aspects of neuronal development, REST and CoREST are not believed to have any direct modulatory roles in glial cell maturation

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Results

Conclusion