The long non-coding RNA (lncRNA) XIST functions as an epigenetic silencer tightly linked to the X chromosome to balance gene expression between the sexes; however, this lncRNA now has a cause for concern as an autosomal gene regulatory function just pushed XIST into a full-blown “X-istential” crisis!
Reports have described a dispersed XIST configuration in many human/monkey/mouse cells (XIST foci detected throughout the nucleus) that associated with “X chromosome dampening,” which downregulates but does not silence X-linked gene expression in cells, including naïve pluripotent stem cells, and associates with failed X chromosome inactivation. Therefore, a fully cognizant team headed by Kathrin Plath (UCLA) suspected that XIST might function beyond the epigenetic inactivation of one X chromosome in female cells.
Let’s hear from Dror, Chitiashvili, and Colleagues on how they unveiled the X-istential crisis of the XIST lncRNA:
- The authors employ RNA fluorescent in situ hybridization (FISH) and RNA antisense purification (RAP)-seq to examine XIST localization across the X chromosome, where it mediates gene expression dampening and chromatin changes in naive human pluripotent stem cells, thereby establishing XIST as the regulator of X chromosome dampening
- X-linked genes regulated to a lesser extent by XIST display increased expression in females; however, genes regulated to a greater extent display similar transcript levels in female and male naive human pluripotent stem cells
- Different regulatory features/chromatin regulation may underlie diverse susceptibility to XIST-mediated dampening
- The endogenous expression of XIST from the X chromosome also spreads to affect autosomal regions, where this lncRNA again alters the chromatin state and dampens target gene expression
- Autosomal target genes lie in close spatial proximity to the genomic XIST locus, suggesting that nuclear organization instructs autosomal localization (like the spread of XIST across the inactive X chromosome)
- While XIST balances X-linked gene dosage between females and males, XIST-mediated repression of autosomal genes prompts male-biased expression and a general imbalance in autosomal gene expression
- XIST induces sexually dimorphic H3K27me3 profiles at autosomal targets, which may prompt epigenetic memory and lasting developmental impacts, as in non-canonical imprinting and inter-generational inheritance
While some may call it an epigenetic X-istential crisis, others see an exciting paradigm shift! These findings now highlight XIST as a regulator of X chromosome dampening and a trans-operating lncRNA when present in a dispersed configuration. Future studies will explore whether autosomal XIST spreading occurs in more cell types and whether this gene regulatory mechanism plays a broad role in development, specific cellular functions, and disease progression.
For more on how the XIST lncRNA may play a critical role in autosomal gene repression, see Cell, January 2024.