Distinct Profiles of REST Interactions with Its Target Genes at Different Stages of Neuronal Development

Abstract

Differentiation of pluripotent embryonic stem (ES) cells through multipotent neural stem (NS) cells into differentiated neurons is accompanied by wholesale changes in transcriptional programs. One factor that is present at all three stages and a key to neuronal differentiation is the RE1-silencing transcription factor (REST/NRSF). Here, we have used a novel chromatin immunoprecipitation-based cloning strategy (SACHI) to identify 89 REST target genes in ES cells, embryonic hippocampal NS cells and mature hippocampus. The gene products are involved in all aspects of neuronal function, especially neuronal differentiation, axonal growth, vesicular transport and release, and ionic conductance. Most target genes are silent or expressed at low levels in ES and NS cells, but are expressed at much higher levels in hippocampus. These data indicate that the REST regulon is specific to each developmental stage and support the notion that REST plays distinct roles in regulating gene expression in pluripotent ES cells, multipotent NS cells, and mature neurons.

REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions

“…53 Two complementary studies have shown differential REST occupancy profiles in ESCs and NSCs and these findings suggested the presence of distinct and overlapping developmental REST regulons. 15,81 For example, one of these studies found 810 and 679 RE1 sites occupied by REST, respectively, in ESCs and NSCs. 15 These included only 32 unique sites in NSCs.…”

Nontelomeric splice variant of telomere repeat-binding factor 2 maintains neuronal traits by sequestering repressor element 1-silencing transcription factor

“…A master repressor, repressor element 1-silencing transcription factor (REST), recruits various corepressors, suppressing neuronal programs in nonneuronal lineages (1)(2)(3)(4)(5)(6)(7). REST binds to a conserved 23-bp motif, repressor element 1 (RE1), of numerous neuronal genes (8,9).…”

“…In addition, Zuccato and colleagues demonstrated that a wild-type huntingtin protein inhibits the repressive effect of REST by sequestering it in the cytoplasm, whereas mutant huntingtin causes an aberrant nuclear accumulation of REST (14,15). Because huntingtin is also expressed in nonneuronal cells, there is an ongoing search for factors that may regulate the functionality of REST, particularly in mature neurons in the adult brain (4,16).…”

MED19 and MED26 Are Synergistic Functional Targets of the RE1 Silencing Transcription Factor in Epigenetic Silencing of Neuronal Gene Expression

“…REST occupies a central role in non-neuronal lineage restriction through its ability to suppress the nonspecific and premature expression of neuronal genes in non-neuronal cells and neural progenitor cells, respectively (4,5,10,11). Consistent with such a role, the expression of REST is dominantly constrained in non-neuronal and neural progenitor cells, although low levels of REST protein are maintained in some populations of postmitotic neurons, most notably those of the hippocampus (10,(12)(13)(14)(15). Functional inactivation of REST in vertebrates leads to early embryonic lethality and ectopic expression of neuronal genes in non-neuronal tissues (16), whereas its forced overexpression causes axon-pathfinding errors (17).…”