DNA Methylation in Neuronal Development and Disease

Bruggeman, Emily C.; Yao, Bing

doi:10.1007/978-3-030-14792-1_5

Cited by 2 publications

(5 citation statements)

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“…However, genespecific promoter DNA methylation pyrosequencing identified the DNA repair genes Ogg1, Apex1, Pnkp and Aptx as hypomethylated in ALS. Few papers report on DNA methylation in human ALS [8]. DNA methylation in sporadic ALS has been examined in disease candidate genes SOD1, vascular endothelial growth factor, angiogenin, and TDP43 [8,96], in members of the metallothione gene family [89], and in the glutamate transporter EAAT2 gene promoter [139].…”

Section: Dna Methylation In Human Alsmentioning

confidence: 99%

“…Few papers report on DNA methylation in human ALS [8]. DNA methylation in sporadic ALS has been examined in disease candidate genes SOD1, vascular endothelial growth factor, angiogenin, and TDP43 [8,96], in members of the metallothione gene family [89], and in the glutamate transporter EAAT2 gene promoter [139]. None of these studies found differences in methylation patterns in sporadic ALS cases compared to control cases.…”

Section: Dna Methylation In Human Alsmentioning

confidence: 99%

“…None of these studies found differences in methylation patterns in sporadic ALS cases compared to control cases. Studies of C9orf72 promoter methylation in sporadic ALS yield contradictory results [8]. A genome-wide analysis of brain DNA methylation in sporadic ALS accomplished by chromatin immunoprecipitation followed by microarray hybridization revealed significant hypermethylation of genes involved in calcium dynamics, oxidative stress, and synapses [90].…”

Section: Dna Methylation In Human Alsmentioning

confidence: 99%

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DNA damage accumulates and responses are engaged in human ALS brain and spinal motor neurons and DNA repair is activatable in iPSC-derived motor neurons with SOD1 mutations

Kim

Jeong

Wong

et al. 2020

acta neuropathol commun

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DNA damage is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, relationships between DNA damage accumulation, DNA damage response (DDR), and upper and lower motor neuron vulnerability in human ALS are unclear; furthermore, it is unknown whether epigenetic silencing of DNA repair pathways contributes to ALS pathogenesis. We tested the hypotheses that DNA damage accumulates in ALS motor neurons along with diminished DDR, and that DNA repair genes undergo hypermethylation. Human postmortem CNS tissue was obtained from ALS cases (N = 34) and age-matched controls without neurologic disease (N = 15). Compared to age-matched controls, abasic sites accumulated in genomic DNA of ALS motor cortex and laser capture microdissection-acquired spinal motor neurons but not in motor neuron mitochondrial DNA. By immunohistochemistry, DNA damage accumulated significantly in upper and lower motor neurons in ALS cases as single-stranded DNA and 8-hydroxy-deoxyguanosine (OHdG) compared to age-matched controls. Significant DDR was engaged in ALS motor neurons as evidenced by accumulation of c-Abl, nuclear BRCA1, and ATM activation. DNA damage and DDR were present in motor neurons at pre-attritional stages and throughout the somatodendritic attritional stages of neurodegeneration. Motor neurons with DNA damage were also positive for activated p53 and cleaved caspase-3. Gene-specific promoter DNA methylation pyrosequencing identified the DNA repair genes Ogg1, Apex1, Pnkp and Aptx as hypomethylated in ALS. In human induced-pluripotent stem cell (iPSC)-derived motor neurons with familial ALS SOD1 mutations, DNA repair capacity was similar to isogenic control motor neurons. Our results show that vulnerable neurons in human ALS accumulate DNA damage, and contrary to our hypothesis, strongly activate and mobilize response effectors and DNA repair genes. This DDR in ALS motor neurons involves recruitment of c-Abl and BRCA1 to the nucleus in vivo, and repair of DNA double-strand breaks in human ALS motor neurons with SOD1 mutations in cell culture.

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Section: Dna Methylation In Human Alsmentioning

confidence: 99%

Section: Dna Methylation In Human Alsmentioning

confidence: 99%

Section: Dna Methylation In Human Alsmentioning

confidence: 99%

See 1 more Smart Citation

DNA damage accumulates and responses are engaged in human ALS brain and spinal motor neurons and DNA repair is activatable in iPSC-derived motor neurons with SOD1 mutations

Kim

Jeong

Wong

et al. 2020

acta neuropathol commun

View full text Add to dashboard Cite

show abstract

“…Changes to the epigenome all ultimately impact gene expression by affecting the level of compaction of chromatin and the ease at which transcriptional machinery can access the DNA strand ( Bowman and Poirier, 2015 ; Bruggeman and Yao, 2019 ). Certain epigenetic marks are associated mainly with facilitating or repressing expression of the associated gene.…”

Section: Introductionmentioning

confidence: 99%

“…Certain epigenetic marks are associated mainly with facilitating or repressing expression of the associated gene. For instance, DNA methylation in promoter regions tend to repress gene transcription, while DNA hydroxymethylation tends to activate gene transcription, again by impacting chromatin compaction ( Bruggeman and Yao, 2019 ). Histone acetylation occurs at lysine residues and generally acts to loosen chromatin allowing access to the DNA strand, thereby increasing transcription rates ( Bowman and Poirier, 2015 ).…”

Section: Introductionmentioning

confidence: 99%