X-Chromosome Dependent Differences in the Neuronal Molecular Signatures and Their Implications in Sleep Patterns

Biological factors and mechanisms that drive sex differences observed in sleep disturbances are understudied and poorly understood. The extent to which sex chromosome constitution impacts on sex differences in circadian patterns is still a knowledge void in the sleep medicine field. Here we focus on the neurological consequences of X-chromosome functional imbalances between males and females and how this molecular inequality might affect sex divergencies on sleep. In light of the X-chromosome inactivation mechanism in females and its implications in gene regulation, we describe sleep-related neuronal circuits and brain regions impacted by sex-biased modulations of the transcriptome and the epigenome. Benefited from recent large-scale genetic studies on the interplay between X-chromosome and brain function, we list clinically relevant genes that might play a role in sex differences in neuronal pathways. Those molecular signatures are put into the context of sleep and sleep-associated neurological phenotypes, aiming to identify biological mechanisms that link X-chromosome gene regulation to sex-biased human traits. These findings are a significant step forward in understanding how X-linked genes manifest in sleep-associated transcriptional networks and point to future research opportunities to address female-specific clinical manifestations and therapeutic responses.