Alternative REST Splicing Underappreciated.

Abstract

As a major orchestrator of the cellular epigenome, the repressor element-1 silencing transcription factor (REST) can either repress or activate thousands of genes depending on cellular context, suggesting a highly context-dependent REST function tuned by environmental cues. While REST shows cell-type non-selective active transcription (Kojima et al., 2001), an N-terminal REST4 isoform caused by alternative splicing, inclusion of an extra exon (N3c) which introduces a pre-mature stop codon, contributes to neurogenesis and tumorigenesis (Palm et al., 1998, 1999; Lee et al., 2000; Raj et al., 2011). Recently, in line with established epigenetic regulation of pre-mRNA splicing (Allo et al., 2010; Luco et al., 2011), we demonstrated that REST undergoes extensive, context-dependent alternative splicing which results in the formation of a large number of mRNA variants predictive of multiple protein isoforms (Chen and Miller, 2013). Supported by the fact that immunoblotting/-staining with different anti-REST antibodies yield different results, alternative splicing allows production of various structurally and functionally different REST protein isoforms in response to shifting physiologic requirements, shedding light on environmental regulation of REST function. However, REST isoforms might be differentially assayed or manipulated, leading to data misinterpretation and controversial findings. For example, in contrast to the proposed neurotoxicity of elevated nuclear REST in ischemia (Noh et al., 2012) and Huntington’s disease (Zuccato et al., 2003; Buckley et al., 2010), Lu et al. recently reported decreased nuclear REST in Alzheimer’s disease and neuroprotection of REST in aging brain (Lu et al., 2014). Unfortunately, alternative REST splicing was largely neglected by Lu et al. (2014), making it necessary for a reevaluation of their findings. As shown in Figure 1 A , human REST gene boundary is now doubled by an alternative …