Cell-Type-Specific mRNA N6-Methyladenosine Landscape and Regulatory Mechanisms Underlying Immune Dysregulation of Sleep-Deprived

Abstract

Sleep deprivation impairs daytime cognitive functioning and is a risk factor for various diseases related to immune dysregulation. N⁶-methyladenosine (m⁶A) is a common epigenetic RNA modification with essential roles in regulating neurogenesis and circadian rhythms. m⁶A dysregulation resulting in immune imbalance has received much attention. In this study, we elucidated the landscape and specific mechanisms of m⁶A regulators in the peripheral blood of patients with sleep deprivation through RNA sequencing and single-cell transcriptomics data sets. We observed that m⁶A regulator upregulation aggravated sleep loss and immune disorders. Women were more sensitive to sleep deprivation. Notably, m⁶A regulator ALKBH5 was downregulated in peripheral blood mononuclear cells (PBMC) of patients with sleep deprivation at the transcriptome level. However, ALKBH5 was cell-type specific upregulated in T cells (TC), B cells (BC), and natural killer (NK) cells, involving the dysregulation of acquired immune mechanisms by aberrant cell–cell communication that mediated ligand–receptor interactions across diverse cell types. Furthermore, the immune dysregulation of sleep loss could be regulated by a potential pathway between ALKBH5 and CD99 in SH-SY5Y and HT22 cells. Sleep deprivation group CD3⁺/CD45⁺ T cells had higher levels of ALKBH5 mRNA than the control group. This study demonstrated that abnormal m⁶A modification patterns caused by m⁶A regulators play a key role in the dysregulation of innate and acquired immunity in sleep deprivation.