Transcription and potential functions of a novel XIST isoform in male peripheral glia

The XIST RNA is known for its critical roles in X Chromosome inactivation (XCI). It is thought to be expressed exclusively from one copy of the X Chromosome and silence it by recruiting various chromatin factors in female cells. In this study, we find XIST expression in male peripheral glia after integrated analyses of single-cell RNA-seq data from multiple human tissues and organs. Single-cell epigenomic data further indicate that the expression is likely driven by an alternative promoter at the end of the first exon, resulting in at least one shorter transcript (referred to as sXIST) that is active in Schwann cells and, moreover, at a higher level in nonmyelinating Schwann cells. This promoter exhibits similar activity in female glia. Multiple lines of evidence from bulk transcriptomic and epigenomic data from peripheral nerve tissues further support these findings. Genes coexpressed positively and strongly with sXIST in male glia show functional enrichment in axon assembly and cilia signaling, with many of them sharing putative miRNA binding sites with sXIST, whereas the negatively correlated genes are enriched for processes important for neuromuscular junctions. This suggests possible functions of sXIST in modulating glia-neuron interactions, perhaps via competitive miRNA binding. This idea is also supported by overexpression analysis of a partial sXIST sequence and the finding of significant XIST expression changes in human cardiomyopathy and polyneuropathy. In summary, the current study suggests a novel, non-XCI role of XIST in peripheral Schwann cells that is mediated by a newly recognized transcript.