ESPE Yearbook of Paediatric Endocrinology

Sci Adv. 2025 Mar 7;11(10):eads8169. doi: 10.1126/sciadv.ads8169

Brief summary: This study explored emerging evidence suggesting that the inactive (or ‘silent’) X chromosome in females may contribute to greater brain resilience compared to males.

The authors used a genetic mouse model to investigate transcriptional activity from the inactive X chromosome (Xi) during aging. By crossing Mus musculus and Mus castaneus strains, distinguished by frequent SNPs, they enabled allele-specific RNA sequencing (RNA-seq). A targeted deletion of the Xist gene on the M. musculus X ensured that the M. castaneus X was consistently inactivated. This setup allowed precise identification of “escapee” genes, those transcribed from the typically silent Xi.

Using single-nucleus RNA-seq, the researchers analyzed over 40,000 hippocampal nuclei from young and aged female mice. Aging altered gene expression of 926 differentially expressed genes (DEGs), including 29 on the X chromosome. When normalized by gene count per chromosome, the X chromosome showed a disproportionately high number of DEGs, especially in dentate gyrus neurons and oligodendrocytes. Gene ontology analysis revealed that X-linked DEGs were enriched in synaptic and neuronal functions, suggesting a specific role for X-linked gene regulation in cognitive aging.

Among the genes upregulated with age on the active X chromosome (Xa) were Dmd, Cnksr2, and Pak3, genes associated with synaptic structure and human intellectual disability. On the Xi, age-related increases in expression were seen in Ftx (a long noncoding RNA involved in XCI and neuroprotection), and in myelination-associated genes such as Plp1 and Gpm6b.

To explore functional consequences, the authors overexpressed Plp1 in the oligodendrocytes of aged mice using adeno-associated virus (AAV). This targeted intervention improved spatial memory in both sexes without altering general activity or anxiety-like behavior, supporting the idea that Xi-derived Plp1 expression can have beneficial cognitive effects.

Despite these findings, the authors caution that single-nucleus RNA-seq has limited sensitivity for low-abundance transcripts like those from the Xi. Thus, complementary computational tools were needed to fully capture Xi activity in aging hippocampal cells.

In summary, the study challenges the view of Xi as transcriptionally silent and suggests that partial reactivation of Xi-linked genes in aging may offer compensatory benefits. This mosaic expression could provide females with a unique resilience to cognitive decline, highlighting the influence of sex chromosomes in brain aging and disease resistance.