DNA Methylation and Its Implications and Accessibility for Neuropsychiatric Therapeutics

Day, Jeremy J.; Kennedy, Andrew; Sweatt, J. David

doi:10.1146/annurev-pharmtox-010814-124527

Cited by 70 publications

(58 citation statements)

References 121 publications

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“…For example, if alterations in intrinsic excitability are critical to the pathogenesis of a specific disorder, then a genome-wide epigenetic therapeutic approach would be a possible avenue for therapeutics. If not, approaches that use zinc finger nucleases (ZFNs), transcriptional activator–like effectors (TALEs), or the clustered regularly interspaced short palindromic repeats (CRISPR)/ Cas9 system (91, 115) to target DNA methylation enzymes to specific genomic sequences would be preferred to limit unintentional consequences on intrinsic excitability.…”

Section: Discussionmentioning

confidence: 99%

Dynamic DNA methylation regulates neuronal intrinsic membrane excitability

et al. 2016

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Epigenetic modifications, such as DNA cytosine methylation, contribute to the mechanisms underlying learning and memory by coordinating adaptive gene expression and neuronal plasticity. Transcription-dependent plasticity regulated by DNA methylation includes synaptic plasticity and homeostatic synaptic scaling. Memory-related plasticity also includes alterations in intrinsic membrane excitability mediated by changes in the abundance or activity of ion channels in the plasma membrane, which sets the threshold for action potential generation. We found that prolonged inhibition of DNA methyltransferase (DNMT) activity increased intrinsic membrane excitability of cultured cortical pyramidal neurons. Knockdown of the cytosine demethylase TET1 or inhibition of RNA polymerase blocked the increased membrane excitability caused by DNMT inhibition, suggesting that this effect was mediated by subsequent cytosine demethylation and de novo transcription. Prolonged DNMT inhibition blunted the medium component of the after-hyperpolarization potential, an effect that would increase neuronal excitability, and was associated with reduced expression of the genes encoding small-conductance Ca2+-activated K+ (SK) channels. Furthermore, the specific SK channel blocker apamin increased neuronal excitability but was ineffective after DNMT inhibition. Our results suggested that DNMT inhibition enables transcriptional changes that culminate in decreased expression of SK channel–encoding genes and decreased activity of SK channels, thus providing a mechanism for the regulation of neuronal intrinsic membrane excitability by dynamic DNA cytosine methylation. This study has implications for human neurological and psychiatric diseases associated with dysregulated intrinsic excitability.

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Section: Discussionmentioning

confidence: 99%

Dynamic DNA methylation regulates neuronal intrinsic membrane excitability

et al. 2016

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“…Other therapeutic strategies targeting DNA methylation include developing drugs that alter the enzymatic activity of the hydroxymethylase TET to normalize 5mC or 5hmC levels, as well as altered activity of Dnmts to treat diseases where DNA methylation levels are perturbed [44,81]. While these strategies are being explored in diseases such as cancer, where deregulated TET enzymes have both tumor suppressing and promoting capabilities [86,183], their potential to treat neurodegenerative diseases is even less known.…”

Section: The Role Of Epigenetic Regulation In Als and Ftdmentioning

confidence: 99%

ALS and FTD: an epigenetic perspective

2016

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two fatal neurodegenerative diseases seen in comorbidity in up to 50% of cases. Despite tremendous efforts over the last two decades, no biomarkers or effective therapeutics have been identified to prevent, decelerate or stop neuronal death in patients. While the identification of multiple mutations in more than two dozen genes elucidated the involvement of several mechanisms in the pathogenesis of both diseases, identifying the hexanuceotide repeat expansion in C9orf72, the most common genetic abnormality in ALS and FTD, opened the door to the discovery of several novel pathogenic biological routes, including chromatin remodeling and transcriptome alteration. Epigenetic processes regulate DNA replication and repair, RNA transcription, and chromatin conformation, which in turn further dictate transcriptional regulation and protein translation. Transcriptional and post-transcriptional epigenetic regulation is mediated by enzymes and chromatin-modifying complexes that control DNA methylation, histone modifications, and RNA editing. While alteration of DNA methylation and histone modification have recently been reported in ALS and FTD, assessment of epigenetic involvement in both diseases is still at an early stage, and the involvement of multiple epigenetic players still needs to be evaluated. As the epigenome serves as a way to alter genetic information not only during aging, but also following environmental signals, epigenetic mechanisms might play a central role in initiating ALS and FTD, especially for sporadic cases. Here, we provide a review of what is currently known about altered epigenetic processes in both ALS and FTD, and discuss potential therapeutic strategies targeting epigenetic mechanisms. As approximately 85% of ALS and FTD cases are still genetically unexplained, epigenetic therapeutics explored for other diseases might represent a profitable direction for the field.

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“…Future studies will continue to further characterize the manner by which neuronal activation modulates the context specific DNA methylation landscape and leads to the complex transcriptional alterations in a panoply memory-related gene targets. Ultimately, future insights into the regulatory relationship between DNA methylation and memory formation may be leveraged to develop neuropsychiatric therapeutic interventions that, through their targeted manipulation of the DNA methylation machinery, ameliorate memory disorders that might owe to perturbed transcriptional regulation within the CNS, such as age-related cognitive decline (Penner and others 2011; Day and others 2015). …”

Section: Realizing Dna Methylation’s Mnemogenic Potential During Cortmentioning

confidence: 99%

DNA Methylation in Memory Formation

Heyward

Sweatt

2015

Neuroscientist

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The establishment of synaptic plasticity and long-term memory requires lasting cellular and molecular modifications that, as a whole, must endure despite the rapid turnover of their constituent parts. Such a molecular feat must be mediated by a stable, self-perpetuating, cellular information storage mechanism. DNA methylation, being the archetypal cellular information storage mechanism, has been heavily implicated as being necessary for stable activity-dependent transcriptional alterations within the central nervous system (CNS). This review details the foundational discoveries from both gene-targeted, as well as whole-genome sequencing, studies that have successfully brought DNA methylation to our attention as a chief regulator of activity- and experience-dependent transcriptional alterations within the CNS. We present a hypothetical framework with which the disparate experimental findings dealing with distinct manipulations of the DNA methylation, and their effect on memory, might be resolved while taking into account the unique impact activity-dependent alterations in DNA methylation potentially have on both memory promoting and memory-suppressing gene expression. And last, we discuss potential avenues for future inquiry into the role of DNA methylation during remote memory formation.

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DNA Methylation and Its Implications and Accessibility for Neuropsychiatric Therapeutics

Cited by 70 publications

References 121 publications

Dynamic DNA methylation regulates neuronal intrinsic membrane excitability

Dynamic DNA methylation regulates neuronal intrinsic membrane excitability

ALS and FTD: an epigenetic perspective

DNA Methylation in Memory Formation

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