Dynamics of DNA Methylation in Aging and Alzheimer's Disease

Irier, Hasan A.; Jin, Peng

doi:10.1089/dna.2011.1565

Cited by 78 publications

(67 citation statements)

References 93 publications

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“…Recent studies have shown that DNA methylation has roles in both disease and normal neuronal function. Once considered to be a stable epigenetic mark that was primarily altered in development and cancer, DNA methylation has now been linked to a wide variety of diseases, including insulin resistance, cardiovascular disease, and neurological disorders (54)(55)(56). In fact, even normal neuronal activity causes rapid changes to DNA methylation.…”

Section: Discussionmentioning

confidence: 99%

Extensive changes in DNA methylation are associated with expression of mutant huntingtin

Yildirim²,

Yap³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

160

126

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The earliest stages of Huntington disease are marked by changes in gene expression that are caused in an indirect and poorly understood manner by polyglutamine expansions in the huntingtin (HTT) protein. To explore the hypothesis that DNA methylation may be altered in cells expressing mutated HTT, we use reduced representation bisulfite sequencing (RRBS) to map sites of DNA methylation in cells carrying either wild-type or mutant HTT. We find that a large fraction of the genes that change in expression in the presence of mutant huntingtin demonstrate significant changes in DNA methylation. Regions with low CpG content, which have previously been shown to undergo methylation changes in response to neuronal activity, are disproportionately affected. On the basis of the sequence of regions that change in methylation, we identify AP-1 and SOX2 as transcriptional regulators associated with DNA methylation changes, and we confirm these hypotheses using genome-wide chromatin immunoprecipitation sequencing (ChIP-Seq). Our findings suggest new mechanisms for the effects of polyglutamine-expanded HTT. These results also raise important questions about the potential effects of changes in DNA methylation on neurogenesis and cognitive decline in patients with Huntington disease.epigenomics | transcription | mRNA-Seq H untington disease (HD) is a fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene, which encodes an abnormally long polyglutamine repeat in the HTT protein. In the early stages of the disease, patients are largely asymptomatic, although they may suffer from mild cognitive impairment and behavioral changes. With time, they develop severe motor dysfunction as well as more pronounced cognitive and psychiatric symptoms. Transcriptional dysregulation is a major component of the early stages of HD, before significant neuronal death. Changes in transcription have been detected in human postmortem tissue (1), mouse models (2-4), and cell culture models (5). Genes reproducibly shown to be differentially expressed across HD models are associated with processes including neurotransmission, neurotrophin receptor signaling, signal transduction, calcium ion transport, synaptic organization, chromatin remodeling, G-protein receptor-coupled signaling, and metabolism (6). The polyglutamine expanded form of HTT may have a direct role in causing these expression changes. A number of DNA-binding proteins have been shown to physically interact with either wild-type or mutant HTT. These include NRSF/REST, CBP, PGC1α, Sp1, BCL11b, p53, LXRα, polycombgroup proteins, SIN3A, and NCOR1 (6). Any effect of HTT on the subcellular localization, activity, or concentration of these proteins would be likely to directly change gene expression.Two lines of evidence suggest that alterations in HTT could also influence DNA methylation. First, histone marks are altered in HD (7-11) and SETD2, a SET domain regulator of H3K36me3, has been previously reported to interact with mutant HTT (12). Due to biochemical...

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Section: Discussionmentioning

confidence: 99%

Extensive changes in DNA methylation are associated with expression of mutant huntingtin

Yildirim²,

Yap³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

160

126

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“…Based on this data, it is thought that the patterns of cytosine modifications acquired throughout neuronal development are critical for proper neurodevelopment and neurological function in the adult brain. In fact, recent studies have implicated epigenetic regulation in both Alzheimer's and Huntington's diseases [7,44,64]. Together, these observations strongly suggest that 5hmC plays a critical role in brain development and related diseases [43].…”

Section: -Hydroxymethylcytosinementioning

confidence: 94%

High-Throughput Sequencing-Based Mapping of Cytosine Modifications

Bernstein

Jin

2015

Epigenetic Technological Applications

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“…As previously mentioned, the recently discovered TET family of dioxygenases is believed to mediate the oxidation of 5mC thereby priming it for removal by the Base Excision Repair pathways (BER) [92]. Disruption of the epigenetic machinery responsible for active demethylation can lead to age-specific 5hmC profiles [138] and/or DNA demethylation profiles [139]. Interestingly, methylation drift is associated with promoter hypomethylation of PSEN1 and APOEgenes important in the age-dependant onset of neurodegenerative diseases such as AD [139].…”

Section: Mechanism Of Age-related Methylation Driftmentioning

confidence: 99%

Epigenetic Changes in Aging and Age-related Disease

Rowbotham¹

2015

Aging Sci

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The epigenome refers to the complete set of heritable chemical modifications made to DNA and histone proteins. Certainly, the most well characterized epigenetic mark is the covalent addition of a methyl group to a CpG dinucleotide site in the genome. The DNA methylome-a collection of methyl marks established during embryogenesis-creates a complex regulatory network involved in cell type differentiation, homeostasis and regulating gene expression in response to environmental stimuli and stress throughout life. Collectively, an increasing body of research supports the notion that over time, diverging methylomes may account for substantial phenotypic discordance in monozygotic-twins and explain disparate susceptibilities to age-related disease. We review this evidence and discuss how a greater insight into the mechanisms of age-related epigenetic dysregulation may inform strategies for molecular diagnostics and therapeutic intervention.

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Dynamics of DNA Methylation in Aging and Alzheimer's Disease

Cited by 78 publications

References 93 publications

Extensive changes in DNA methylation are associated with expression of mutant huntingtin

Extensive changes in DNA methylation are associated with expression of mutant huntingtin

High-Throughput Sequencing-Based Mapping of Cytosine Modifications

Epigenetic Changes in Aging and Age-related Disease

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