DNA Methylation Profiling of Human Prefrontal Cortex Neurons in Heroin Users Shows Significant Difference between Genomic Contexts of Hyper- and Hypomethylation and a Younger Epigenetic Age

Kozlenkov, Alexey; Jaffe, Andrew E.; Timashpolsky, Alisa; Apontes, Pasha; Rudchenko, Sergei; Barbu, Mihaela; Byne, William; Hurd, Yasmin L.; Horvath, Steve; Dracheva, Stella

doi:10.3390/genes8060152

Cited by 75 publications

(66 citation statements)

References 98 publications

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“…Next, we independently validated our top aging-DMCGs using another public cohort of NeuN-sorted prefrontal cortex brain samples [ 61 ]. From this dataset (GSE98203), we only used healthy, NeuN-positive controls as NeuN-negative data was not available.…”

Section: Resultsmentioning

confidence: 99%

DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex

Gasparoni

Bultmann

Lutsik

et al. 2018

Epigenetics & Chromatin

182

180

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BackgroundEpigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer’s disease (AD). However, strong variation of cell-type proportions across brain tissue samples represents a significant source of data noise. Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues.ResultsWe show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort. We identify numerous genes with cell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as CLU, SYNJ2 and NCOR2 or in glia RAI1,CXXC5 and INPP5A. Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as MCF2L, ANK1, MAP2, LRRC8B, STK32C and S100B. A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., HOXA3 or glia (ANK1). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes APP and ADAM17.ConclusionsOur data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.Electronic supplementary materialThe online version of this article (10.1186/s13072-018-0211-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex

Gasparoni

Bultmann

Lutsik

et al. 2018

Epigenetics & Chromatin

182

180

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“…Epigenetic changes in the brain may be highly localized, as studies utilizing whole brain tissue have often reported no significant change in global DNA methylation levels following morphine exposure 19,20 . Targeted approaches have proven more insightful, identifying changes in regions of the brain associated with addiction such as the hippocampus, medial prefrontal cortex and VTA in a rat model of heroin self-administration and reward devaluation 21 and post-mortem orbitofrontal cortex brain tissue from former heroin users 22 .…”

Section: Introductionmentioning

confidence: 99%

The effect of morphine upon DNA methylation in ten regions of the rat brain

Barrow

Byun

et al. 2017

Epigenetics

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A and Guo, L (2017) The effect of morphine upon DNA methylation in ten regions of the rat brain. Epigenetics, 12 (12 AbstractMorphine is one of the most effective analgesics in medicine. However, its use is associated with the development of tolerance and dependence. Recent studies demonstrating epigenetic changes in the brain after exposure to opiates have provided insight into mechanisms possibly underlying addiction. In this study, we sought to identify epigenetic changes in ten regions of the rat brain following acute and chronic morphine exposure. We analyzed DNA methylation of six nuclear-encoded genes implicated in brain function (Bdnf, Comt, Il1b, Il6, Nr3c1 and Tnf) and three mitochondrially-encoded genes (Mtco1, Mtco2 and Mtco3), and measured global 5-methylcytosine (5-mc) and 5-hydroxymethylcytosine (5-hmc) levels. We observed differential methylation of Bdnf and Il6 in the pons, Nr3c1 in the cerebellum, and Il1b in the hippocampus in response to acute morphine exposure (all p<0.05). Chronic exposure was associated with differential methylation of Bdnf and Comt in the pons, Nr3c1 in the hippocampus and Il1b in the medulla oblongata (all p<0.05). Global 5-mc levels significantly decreased in the superior colliculus following both acute and chronic morphine exposure, and increased in the hypothalamus following chronic exposure. Chronic exposure was also associated with significantly increased global 5-hmc levels in the cerebral cortex, hippocampus and hypothalamus, but significantly decreased in the midbrain. Our results demonstrate, for the first time, highly localized epigenetic changes in the rat brain following acute and chronic morphine exposure. Further work is required to elucidate the potential role of these changes in the formation of tolerance and dependence.

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“…S12B-C). Using CG dinucleotides that exhibited methylation changes statistically associated with aging neurons from human prefrontal cortex ( 46 ), we found some direct overlap with DRHs and a closer relative distance than random (fig. S12D-E).…”

Section: Main Textmentioning

confidence: 93%

Incorporation of a nucleoside analog maps genome repair sites in post-mitotic human neurons

Reid

Reed

Schlachetzki

et al. 2020

Preprint

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One Sentence Summary: 3Recurrent DNA repair hotspots in neurons are linked to genes essential for identity and 4 function. 5 6 Abstract: 7 Neurons are the longest-living cells in our bodies, becoming post-mitotic in early 8 development upon terminal differentiation. Their lack of DNA replication makes them reliant on 9 DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, 10 potentially giving rise to genomic dysfunction that may influence cognitive decline and 11 neurodegenerative diseases. Despite this challenge, our knowledge of how genome instability 12 emerges and what mechanisms neurons and other long-lived cells may have evolved to protect 13 their genome integrity over the human life span is limited. Using a targeted sequencing approach, 14we demonstrate that neurons consolidate much of their DNA repair efforts into well-defined 15 hotspots that protect genes that are essential for their identity and function. Our findings provide a 16 basis to understand genome integrity as it relates to aging and disease in the nervous system. 17 18 Main Text: 19Neurons are highly specialized post-mitotic cells comprising the major functional cell type 20 of the central nervous system. While there is a limited capacity to generate new neurons throughout 21 life, the majority of neurons age in parallel with the organism, making them especially susceptible 22to decline from age-related disruptions in cellular homeostasis (1, 2). Neurons must repair ~10 4-5 23

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DNA Methylation Profiling of Human Prefrontal Cortex Neurons in Heroin Users Shows Significant Difference between Genomic Contexts of Hyper- and Hypomethylation and a Younger Epigenetic Age

Cited by 75 publications

References 98 publications

DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex

DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex

The effect of morphine upon DNA methylation in ten regions of the rat brain

Incorporation of a nucleoside analog maps genome repair sites in post-mitotic human neurons

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