Alternative REST Splicing Underappreciated
bepress|Life Sciences|Biology | bepress|Life Sciences|Genetics and Genomics|Genomics
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, an N-terminal REST4 isoform caused by alternative splicing - inclusion of an extra exon (N3c) which introduces a pre-mature stop codon - has been implicated in neurogenesis and tumorigenesis. Recently, in line with established epigenetic regulation of pre-mRNA splicing, 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. Supported by that immunoblotting/-staining with different anti-REST antibodies yield inconsistent results, alternative splicing allows production of various structurally and functionally different REST protein isoforms in response to shifting physiological requirements, providing a reasonable explanation for the diverse, highly context-dependent 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 and Huntington's disease, Lu et al. recently reported decreased nuclear REST in Alzheimer's disease and neuroprotection of REST in ageing brain. Unfortunately, alternative REST splicing was largely neglected by Lu et al., making it necessary for a re-evaluation of their findings.