5-hydroxymethylcytosine is dynamically regulated during forebrain organoid development and aberrantly altered in Alzheimer’s disease

Abstract

5-hydroxymethylcytosine (5hmC) undergoes dynamic changes during mammalian brain development, and its dysregulation is associated with Alzheimer's disease (AD). The dynamics of 5hmC during early human brain development and how they contribute to AD pathologies remain largely unexplored. We generate 5hmC and transcriptome profiles encompassing several developmental time points of healthy forebrain organoids and organoids derived from several familial AD patients. Stage-specific differentially hydroxymethylated regions demonstrate an acquisition or depletion of 5hmC modifications across developmental stages. Additionally, genes concomitantly increasing or decreasing in 5hmC and gene expression are enriched in neurobiological or early developmental processes, respectively. Importantly, our AD organoids corroborate cellular and molecular phenotypes previously observed in human AD brains. 5hmC is significantly altered in developmentally programmed 5hmC intragenic regions in defined fetal histone marks and enhancers in AD organoids. These data suggest a highly coordinated molecular system that may be dysregulated in these early developing AD organoids.

An Epigenetic Role of Mitochondria in Cancer

“…DNA methylation also regulates the neurodegenerative process. The dysregulation of 5hmC during brain development, including different 5hmC concentrations, affects gene regulation in neurodegenerative processes, and the reduction in TET activity in parallel with the reduction of 5hmC concentrations promotes neurodegeneration in the mouse model of Alzheimer’s disease [ 347 , 348 , 349 , 350 ].…”

Dementia with Lewy bodies post-mortem brains reveal differentially methylated CpG sites with biomarker potential

“…Although we didn’t replicate most of the previously reported DLB signals at stringent significance thresholds (q-value < 0.05 or p -value < 9e-8), we were able to detect several new signals/genes reported to be associated with other neurodegenerative diseases such as PD and AD. Another limitation of our study is the inability of the standard sodium bisulfite conversion method used in the MethylationEPIC array analysis to distinguish between 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), with the latter being enriched in brain cells and thought to play an important role in neural development and neurodegenerative diseases 61 , 62 . Parallel profiling of methylation and hydroxymethylation 63 or oxidative bisulfite sequencing 64 might be feasible solutions for capturing intermediary DNA methylation states between methylated and unmethylated cytosine.…”

Current progress of cerebral organoids for modeling Alzheimer's disease origins and mechanisms

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