NRSF and Its Epigenetic Effectors: New Treatments for Neurological Disease

Abstract

The Neuron Restrictive Silencer Factor (NRSF) is the well-known master transcriptional repressor of the neuronal phenotype. Research to date has shown that it is an important player in the growth and development of the nervous system. Its role in the maturation of neural precursor cells to adult neurons has been well characterized in stem cell models. While much has been characterized from a developmental perspective, research is revealing that NRSF plays a role in various neurological diseases, ranging from neurodegenerative, neuropsychiatric, to cancer. Dysregulation of NRSF activity disrupts downstream gene expression that is responsible for neuronal cell homeostasis in several models that contribute to pathologic states. Interestingly, it is now becoming apparent that the dysregulation of NRSF contributes to neurological disease through epigenetic mechanisms. Although NRSF itself is a transcription factor, its major effectors are chromatin modifiers. At the level of epigenetics, changes in NRSF activity have been well characterized in models of neuropathic pain and epilepsy. Better understanding of the epigenetic basis of brain diseases has led to design and use of small molecules that can prevent NRSF from repressing gene expression by neutralizing its interactions with its chromatin remodelers. This review will address the basic function of NRSF and its cofactors, investigate their mechanisms, then explore how their dysfunction can cause disease states. This review will also address research on NRSF as a therapeutic target and delve into new therapeutic strategies that focus on disrupting NRSF's ability to recruit chromatin remodelers.

Keywords: epigenetics; neurological disease; neuron restrictive silencer factor.

Figure 1

Neuron Restrictive Silencer Factor (NRSF) recruits multiple chromatin modifiers. The major function of NRSF is to recruit chromatin modifiers to neural genes by recognizing NRSEs throughout the genome. At the N-terminal end, NRSF recruits mSin3 enabling recruitment of histone deacetylase activity. Further histone deacetylase activity is conferred through recruitment of the major corepressor, CoREST, at the C-terminal end. Additionally, REST corepressor 1 (CoREST) recruits the histone demethylase LSD1. NRSF can also recruit the histone methylation activity of G9a. This is indirect through recruitment of chromodomain containing protein, chromodomain Y-like (CDYL).

Figure 2

Inhibiting the Chromatin Modifying Effectors of NRSF. Inhibition of mSin3 recruitment by NRSF at the N-terminal end has been shown using molecules that mimic the helix structure of NRSF that recruits mSin3. At the C-terminal end of NRSF, small molecules against the major corepressor of NRSF, CoREST, can inhibit both deacetylase and demethylase activity.