Diurnal and seasonal molecular rhythms in human neocortex and their relation to Alzheimer’s disease

Abstract

Circadian and seasonal rhythms are seen in many species, modulate several aspects of human physiology, including brain functions such as mood and cognition, and influence many neurological and psychiatric illnesses. However, there are few data regarding the genome-scale molecular correlates underlying these rhythms, especially in the human brain. Here, we report widespread, site-specific and interrelated diurnal and seasonal rhythms of gene expression in the human brain, and show their relationship with parallel rhythms of epigenetic modification including histone acetylation, and DNA methylation. We also identify transcription factor-binding sites that may drive these effects. Further, we demonstrate that Alzheimer's disease pathology disrupts these rhythms. These data suggest that interrelated diurnal and seasonal epigenetic and transcriptional rhythms may be an important feature of human brain biology, and perhaps human biology more broadly, and that changes in such rhythms may be consequences of, or contributors to, diseases such as Alzheimer's disease.

Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex

“…The epigenetic mechanisms involved in the diurnal rhythms of the cerebral cortex are less well characterized; however, increasing evidence indicates a role for DNA methylation in these rhythms. In contrast to the historically accepted view of DNA methylation as a stably maintained epigenetic mark, approximately 6% (25,476) of CpG sites assayed by 450k array are dynamically regulated throughout diurnal and seasonal cycles 9 . This epigenetic plasticity plays an important role in circadian entrainment and the resiliency of the circadian clock to changes in the diurnal environment [10][11][12] .…”

DNA Methylation Network Estimation with Sparse Latent Gaussian Graphical Model

“…In addition to standard quality control, age at death, sex, batch, post mortem interval, and top 10 principal components (PC) from the DNA methylation data were regressed out. For method evaluation, we used gene expression data (13,484 genes) from 508 individuals of the ROSMAP study [17].…”

Untitled

“…This was extensively reviewed, showing that circadian oscillations were associated with corresponding changes in H3K9ac and, additionally, H3K27ac and also the trimethylated form, H3K4me3 [66]. In post-mortem human brains, the H3 acetylome revealed a widespread rhythmicity, which was, moreover, reduced in amplitude in AD patients [67]. The aforementioned antagonism between acetylation by CLOCK and deacetylation by SIRT1 has a specific role in cellular oscillators [21, 68,69], but also extends to the control of other circadian-driven genes [66].…”