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Rhythmic Regulation of DNA Methylation by BMAL1 is Altered in Alzheimer's Disease


Alzheimer’s disease (AD) is on the rise in the U.S. and has no current cure or effective, lasting therapy. AD is associated with circadian and epigenetic disruptions, both of which may contribute to the neurodegeneration, cognitive impairment and dementia characteristic of AD. Epigenetic machinery is known to regulate the circadian clock, however preliminary studies in our lab have suggested that circadian regulators may also regulate epigenetic machinery. We explored the relationship between DNA methylation and circadian molecular mechanisms in the context of AD. Specifically, we investigated the action of circadian regulator Bmal1 in mediating the expression of DNA methyltransferase 1 (Dnmt1) in rat neurons. We hypothesized that a) Dnmt1 is expressed rhythmically in neurons, that b) Bmal1 acts as a transcription factor to regulate oscillation of Dnmt1, and that c) AD pathology alters this rhythmicity and regulation of Dnmt1. To generate an in vitro model of AD, amyloid precursor protein (APP) was overexpressed in adult rat hippocampal neurons. Dnmt1 transcription in the rat neurons was indeed found to be rhythmic and appeared to be altered in APP-overexpressing neurons. Additionally, we showed that Bmal1 does rhythmically bind to canonical E-boxes present at the Dnmt1 gene and that this binding is largely reduced with APP-overexpression. Our results not only provide an example of direct circadian control of DNA methylation in neurons, but also support our hypothesis that AD pathology disrupts this regulation. Defining the mechanism behind this relationship may further elucidate the molecular effects of AD pathology, as well as reveal possible circadian targets as future AD therapeutics.

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