The many faces of REST oversee epigenetic programming of neuronal genes

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Nervous system development relies on a complex signaling network to engineer the orderly transitions that lead to the acquisition of a neural cell fate. Progression from the non-neuronal pluripotent stem cell to a restricted neural lineage is characterized by distinct patterns of gene expression, particularly the restriction of neuronal gene expression to neurons. Concurrently, cells outside the nervous system acquire and maintain a non-neuronal fate that permanently excludes expression of neuronal genes. Studies of the transcriptional repressor REST, which regulates a large network of neuronal genes, provide a paradigm for elucidating the link between epigenetic mechanisms and neurogenesis. REST orchestrates a set of epigenetic modifications that are distinct between non-neuronal cells that give rise to neurons and those that are destined to remain as nervous system outsiders.

Introduction

Epigenetic regulation is a compelling mechanism for controlling developmental events [1, 2]. In this form of regulation, distinct patterns of gene expression are inherited by chromatin modifications, such as DNA and histone methylation, that do not involve changes in DNA sequence. Neurogenesis, a process central to vertebrate development, requires the acquisition of neural cell fates within the developing nervous system and, in parallel, maintenance of non-neural cell fates outside the nervous system [3]. These two complementary events must be coordinated precisely for correct formation of the nervous system. Furthermore, neurogenesis requires that, within the developing nervous system, only post-mitotic neurons will express neuronal genes, because neural stem cells or progenitors have not yet committed to a neural lineage [4]. These requirements raise the fundamental question of how neuronal gene chromatin is epigenetically programmed in different cellular contexts. How, for example, does neuronal gene chromatin in non-neural cells, where neuronal genes are never expressed, compare to that in neurons where these genes are expressed? In multipotent neural stem or progenitor cells, neuronal genes are repressed, but the cells have the capacity for subsequent expression in response to a developmental signal. Does neuronal gene chromatin in the progenitors reflect a state that is intermediate between suppression and activation, or is there a switch between a silenced and active state upon differentiation? Finally, what is the status of neuronal gene chromatin in pluripotent embryonic stem (ES) cells that have the unique capacity to differentiate into all cell lineages of the developing embryo?

For the establishment of epigenetic modifications representing distinct stages of differentiation, chromatin modifiers, such as DNA methyltransferases, histone methyltransferases and histone acetyltransferases, are recruited to specific genomic loci by DNA binding proteins, either repressors or activators [5]. A compelling candidate for orchestrating epigenetic events is the DNA binding protein, REST (RE1 silencing transcription factor; also called NRSF). REST was discovered in 1995 as a repressor of neuronal genes containing a 23 bp conserved motif, known as RE1 (repressor element 1 or NRSE) [6, 7]. Several lines of evidence now point to REST as a key protein for regulating the large network of genes essential for neuronal function [8]. Here, we discuss the most recent studies on epigenetic mechanisms, orchestrated by REST, that characterize specific stages of mammalian neurogenesis.

Section snippets

Wiring a genetic network for permanent silencing of neuronal genes outside the nervous system

REST is obligatory for the correct development of vertebrates, because perturbation of REST expression or function in the developing embryo results in ectopic expression of neuronal genes in non-neuronal tissues and early embryonic lethality [9]. In terminally differentiated non-neuronal tissue, neuronal genes are presumably in a long-term silencing state. How does REST direct this mode of silencing? The answer lies in part with its signature functional domains. REST harbors three functional

Programming a poised status for neuronal gene chromatin in pluripotent embryonic stem cells

The silencing of neuronal gene chromatin in differentiated non-neuronal cells is stable, inheritable and endures the lifetime of the animal. By contrast, embryonic stem cells, although also non-neuronal, still have the capacity for self-renewal and differentiation along all cell lineages. The question arises as to whether these two fundamentally different non-neuronal cell types utilize similar epigenetic mechanisms to suppress the same neuronal genes? If so, ES cells and, presumably, neural

Plasticity versus stability of neuronal gene chromatin, a glance at the outcome

The repression of neuronal gene expression in differentiated non-neuronal and ES cells is associated with two different epigenetic states. Although both states involve HDAC, the consequences for neuronal gene expression are quite different. In particular, whereas there is no basal transcription of several neuronal genes in differentiated non-neuronal cells, these same genes are transcribed at low levels in ES cells [27••]. Furthermore, perturbation of HDAC activity, a modifier associated with

The chromatin state at terminal differentiation: neurons at last

The transition from stem or progenitor cell to a post-mitotic neuron requires disarming REST. During cortical differentiation, post-translational degradation of the REST protein precedes both its dismissal from RE1 sites and transcriptional inactivation of the REST gene itself at terminal differentiation [27••] (Figure 2). The identity of transcriptional activators that might function after REST departure is not known, but a novel neuronal protein, termed inhibitor of BRAF35 (iBRAF), is an

Conclusions and future directions

Epigenetic regulation of neuronal gene chromatin by REST is fundamental for maintaining stem cells in an undifferentiated pluripotent state and for proper acquisition of neural fate during neurogenesis. The disappearance of REST during cortical neurogenesis appears to be a prerequisite for normal neuronal function in the adult. Are there any situations under which REST is re-expressed in mature neurons and, if so, what are the consequences?

Previous in situ hybridization studies of adult rat

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors thank J Chenoweth IV and R Shiekhattar for permitting us to cite unpublished work, and J Speh for help with the figures. We apologize for omitted citations due to space limitations. G Mandel is an investigator of the Howard Hughes Medical Institute. We acknowledge support from a National Institutes of Health grant to G Mandel.

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