Role of 5-hydroxymethylcytosine in neurodegeneration

Sherwani, Shariq I.; Khan, Haseeb A.

doi:10.1016/j.gene.2015.06.052

Cited by 67 publications

(43 citation statements)

References 114 publications

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“…Despite an emerging role of cytosine hydroxymethylation in neurodegenerative diseases 46 , no studies to date have examined the putative epigenetic role of 5hmC in regulating the C9orf72 promoter activity in ALS. To distinguish between 5mC and 5hmC residues at the C9orf72 promoter at different stages of reprogramming and differentiation, we used a 5hmC sensitive MspI/HpaII restriction digest of genomic DNA followed by qPCR.…”

Section: Resultsmentioning

confidence: 99%

C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells

Esanov

Belle

Blitterswijk

et al. 2016

Experimental Neurology

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Amongst several genetic mutations known to cause amyotrophic lateral sclerosis (ALS), a hexanucleotide repeat expansion in the C9orf72 gene is the most common. In approximately 30% of C9orf72-ALS cases, 5-methylcytosine (5mC) levels within the C9orf72 promoter are increased, resulting in a modestly attenuated phenotype. The developmental timing of C9orf72 promoter hypermethylation and the reason why it occurs in only a subset of patients remains unknown. In order to model the acquisition of C9orf72 hypermethylation and examine the potential role of 5-hydroxymethylcytosine (5hmC), we generated induced pluripotent stem cells (iPSCs) from an ALS patient with C9orf72 promoter hypermethylation. Our data show that 5mC levels are reduced by reprogramming and then re-acquired upon neuronal specification, while 5hmC levels increase following reprogramming and are highest in iPSCs and motor neurons. We confirmed the presence of 5hmC within the C9orf72 promoter in post-mortem brain tissues of hypermethylated patients. These findings show that iPSCs are a valuable model system for examining epigenetic perturbations caused by the C9orf72 mutation and reveal a potential role for cytosine demethylation.

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Section: Resultsmentioning

confidence: 99%

C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells

Esanov

Belle

Blitterswijk

et al. 2016

Experimental Neurology

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“…Studies assessing 5mC and 5hmC content in different neurodegenerative pathologies, including Alzheimer's and Huntington's diseases, haven been reviewed in past years [108]. The levels of 5hmC in brain increase progressively from birth until death [108], and this age-associated increase was significantly higher in an Alzheimer transgenic mice model [109], while there is a disease-associated decrease of 5hmC levels in different brain regions in patients with the same condition [108]. One example that illustrates the importance of 5hmC in maintaining cell phenotype is liver fibrosis.…”

Section: Perspectives and Concluding Remarksmentioning

confidence: 99%

5-Hydroxymethylcytosine (5hmC), or How to Identify Your Favorite Cell

2018

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Abstract:Recently described as the sixth base of the DNA macromolecule, the precise role of 5-hydroxymethylcytosine (5hmC) is the subject of debate. Early studies indicate that it is functionally distinct from cytosine DNA methylation (5mC), and there is evidence for 5hmC being a stable derivate of 5mC, rather than just an intermediate of demethylation. Moreover, 5hmC events correlate in time and space with key differentiation steps in mammalian cells. Such events span the three embryonic germ layers and multiple progenitor cell subtypes, suggesting a general mechanism. Because of the growing understanding of the role of progenitor cells in disease origin, we attempted to provide a detailed summary on the currently available literature supporting 5hmC as a key player in adult progenitor cell differentiation. This summary consolidates the emerging role for 5hmC in defining cellular fate.

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“…Growing evidence now show that 5hmCs, initially thought to represent an intermediate state between methylated DNA and unmethylated DNA, also act as a stable epigenetic marker that might contribute to neurological disease development [164,166]. Of interest, studies using human and mouse tissues have shown that the number of 5hmC sites increase with age and levels vary across organs [30,66,170].…”

Section: Epigenetic Regulatory Mechanismsmentioning

confidence: 99%

“…DNA methylation studies characterizing changes in 5hmC levels in many neurodegenerative diseases aim to identify whether these changes may serve as potential biomarkers or therapeutic targets for those diseases [3]. Interestingly, involvement of 5hmC level changes and regulation of transcription factors have been reported in neurodevelopment, neurodevelopmental diseases, aging, and neurodegenerative diseases [164,166], suggesting these DNA marks are important for neuronal cell development and maintenance.…”

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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Role of 5-hydroxymethylcytosine in neurodegeneration

Cited by 67 publications

References 114 publications

C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells

C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells

5-Hydroxymethylcytosine (5hmC), or How to Identify Your Favorite Cell

ALS and FTD: an epigenetic perspective

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