Novel inactive X-linked lncRNAs

Although only ~2% of our genome encodes protein coding genes, ~70% of the genome is transcribed. Emerging evidence suggests that long non-protein coding (lnc) RNAs constitute a significant proportion of transcribed RNAs in eukaryotic cells. The function of most lncRNAs, however, remains unknown. X-inactivation provides a paradigm to elucidate principles of how lncRNAs function. X-chromosomal lncRNAs are believed to orchestrate the divergent transcriptional fates of the two X-chromosomes in females (e.g., Xist RNA).

Our prior work further predicts lncRNAs in addition to Xist RNA are required for X-inactivation (Kalantry et al., 2009; Maclary et al., 2017). Through a screen for inactive X-expressed lncRNAs, we recently discovered novel lncRNAs that are exclusively expressed from the mouse inactive X-chromosome. An example of such lncRNAs is an antisense Xist lncRNA that is required to activate Xist (XistAR; Sarkar et al., 2015). Another lncRNA, Xist2, coats the inactive-X like Xist RNA, albeit in a smaller domain compared to Xist RNA. Ongoing and future work aims to dissect the roles of XistAR, Xist2, Xist3, and other novel inactive X-linked lncRNAs in X-inactivation. An understanding of lncRNA function in X-inactivation offers the possibility of elucidating principles of lncRNA function broadly, both during tissue homeostasis and in diseases.