X-chromosome inactivation (XCI) equalizes X-linked gene dosage between XX females and XY males in eutherian mammals and is canonically initiated by the long noncoding RNA Xist, which coats one X chromosome and recruits Polycomb-mediated chromatin silencing. Xist expression has therefore been considered female-specific and central to balancing gene dosage between two X chromosomes in females and a single X chromosome in males. However, emerging evidence suggests that Xist can also be expressed in male cells in both healthy and pathogenic contexts, raising fundamental questions about the scope and constraints of Xist function. Here, we identify robust Xist expression in somatic cells of male white-footed deermice (Peromyscus leucopus), a placental mammal with a conventional XY karyotype. Unlike the chromosome-wide Xist RNA coating observed in females, male Xist RNA localizes as discrete nuclear puncta and is detected across multiple tissues by RNA-seq, RT-qPCR, and RNA fluorescence in situ hybridization. Integrative transcriptomic and chromatin profiling using CUT&Tag and single-nucleus Paired-Tag reveals that male Xist expression is not merely incidental but has measurable regulatory consequences. In females, Xist expression is associated with chromosome-wide enrichment of the repressive histone mark H3K27me3 and transcriptional silencing of X-linked genes. In males, although Xist transcription is also associated with H3K27me3, this interaction does not induce global X-chromosome inactivation. Instead, Xist selectively represses a subset of dosage-sensitive neural and mitochondrial X-linked genes, while the majority of X-linked genes remain largely active. Notably, with persistent Xist activity, neither males nor females achieve complete X-to-autosome dosage compensation in P. leucopus. These findings establish P. leucopus as a mammalian system in which male Xist operates outside the canonical female-specific XCI pathway, revealing a gene-selective model of X-chromosome regulation. Our results challenge the universality of prevailing XCI models and suggest that partial, context-dependent Xist activity represents a viable and evolutionarily stable dosage compensation strategy in mammals.
Andrade Ludena, M. D., Duong, J. V., Barbour, A. G., Hartl, C., Long, A. D., Sun, S., Motiwala, A.
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