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24-hour rhythms of DNA methylation and their relation with rhythms of RNA expression in the human dorsolateral prefrontal cortex.

Lim AS, Srivastava GP, Yu L, Chibnik LB, Xu J, Buchman AS, Schneider JA, Myers AJ, Bennett DA, De Jager PL - PLoS Genet. (2014)

Bottom Line: We then related rhythms of DNA methylation with rhythms of RNA expression determined by RNA sequencing.We found evidence of significant 24-hour rhythmicity of DNA methylation.Regions near transcription start sites were enriched for high-amplitude rhythmic DNA methylation sites, which were in turn time locked to 24-hour rhythms of RNA expression of nearby genes, with the nadir of methylation preceding peak transcript expression by 1-3 hours.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
Circadian rhythms modulate the biology of many human tissues, including brain tissues, and are driven by a near 24-hour transcriptional feedback loop. These rhythms are paralleled by 24-hour rhythms of large portions of the transcriptome. The role of dynamic DNA methylation in influencing these rhythms is uncertain. While recent work in Neurospora suggests that dynamic site-specific circadian rhythms of DNA methylation may play a role in modulating the fungal molecular clock, such rhythms and their relationship to RNA expression have not, to our knowledge, been elucidated in mammalian tissues, including human brain tissues. We hypothesized that 24-hour rhythms of DNA methylation exist in the human brain, and play a role in driving 24-hour rhythms of RNA expression. We analyzed DNA methylation levels in post-mortem human dorsolateral prefrontal cortex samples from 738 subjects. We assessed for 24-hour rhythmicity of 420,132 DNA methylation sites throughout the genome by considering methylation levels as a function of clock time of death and parameterizing these data using cosine functions. We determined global statistical significance by permutation. We then related rhythms of DNA methylation with rhythms of RNA expression determined by RNA sequencing. We found evidence of significant 24-hour rhythmicity of DNA methylation. Regions near transcription start sites were enriched for high-amplitude rhythmic DNA methylation sites, which were in turn time locked to 24-hour rhythms of RNA expression of nearby genes, with the nadir of methylation preceding peak transcript expression by 1-3 hours. Weak ante-mortem rest-activity rhythms were associated with lower amplitude DNA methylation rhythms as were older age and the presence of Alzheimer's disease. These findings support the hypothesis that 24-hour rhythms of DNA methylation, particularly near transcription start sites, may play a role in driving 24-hour rhythms of gene expression in the human dorsolateral prefrontal cortex, and may be affected by age and Alzheimer's disease.

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The effects of sex, age, Alzheimer's disease, and 24-hour activity rhythms on the timing of rhythms of methylation.Circular histograms of the effect of clinical variables on the timing of the nadir of methylation of 21,282 high amplitude DNA methylation sites, in 1 hour bins. P-values determined using Rao's Test for the equality of polar directions. Dark lines indicate angular means. (A) Female vs. Male Sex. (B) Age above vs. below median (88.4 years). (C) Present vs. absent Alzheimer's Disease based on NIA-Reagan Criteria (intermediate/high = present; low/no = absent). (D) High vs. low actigraphic rhythmicity based on 24-hour activity rhythms determined ante-mortem in a subset of 134 participants by actigraphy and quantified using the interdaily stability metric as described in the text. Female sex, higher age, and absence of dementia were associated with an earlier timing of methylation nadirs.
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pgen-1004792-g006: The effects of sex, age, Alzheimer's disease, and 24-hour activity rhythms on the timing of rhythms of methylation.Circular histograms of the effect of clinical variables on the timing of the nadir of methylation of 21,282 high amplitude DNA methylation sites, in 1 hour bins. P-values determined using Rao's Test for the equality of polar directions. Dark lines indicate angular means. (A) Female vs. Male Sex. (B) Age above vs. below median (88.4 years). (C) Present vs. absent Alzheimer's Disease based on NIA-Reagan Criteria (intermediate/high = present; low/no = absent). (D) High vs. low actigraphic rhythmicity based on 24-hour activity rhythms determined ante-mortem in a subset of 134 participants by actigraphy and quantified using the interdaily stability metric as described in the text. Female sex, higher age, and absence of dementia were associated with an earlier timing of methylation nadirs.

Mentions: A number of clinical factors such as age [12], sex [13], [14], and presence of Alzheimer's disease [15] have been described to impact 24-hour rhythms. Moreover, dorsolateral prefrontal cortex molecular 24-hour rhythms may plausibly reflect or impact observed behavioral 24-hour rhythms. We therefore examined the impact of these factors on the amplitude and timing of 21,282 high amplitude DNA methylation sites (including intergenic sites). We assessed the effect of these variables on the parameters of DNA methylation rhythmicity by considering extended cosine models of the form M = m+(β1+β2x)*cos(t−βA−βBx) [Eq3] where x represents high vs. low age, male vs. female sex, present vs. absent Alzheimer's disease, or high vs. low behavioral rhythmicity, β2 reflects the effect of x on amplitude, and βB reflects the effect of x on phase. Female sex, higher age, and absence of dementia were associated with an earlier average phase of rhythms of methylation (Figure 6) while the presence of Alzheimer's disease, female sex, higher age, and lower ante-mortem actigraphic rhythmicity were associated with a lower average amplitude of methylation rhythms (Figure 7).


24-hour rhythms of DNA methylation and their relation with rhythms of RNA expression in the human dorsolateral prefrontal cortex.

Lim AS, Srivastava GP, Yu L, Chibnik LB, Xu J, Buchman AS, Schneider JA, Myers AJ, Bennett DA, De Jager PL - PLoS Genet. (2014)

The effects of sex, age, Alzheimer's disease, and 24-hour activity rhythms on the timing of rhythms of methylation.Circular histograms of the effect of clinical variables on the timing of the nadir of methylation of 21,282 high amplitude DNA methylation sites, in 1 hour bins. P-values determined using Rao's Test for the equality of polar directions. Dark lines indicate angular means. (A) Female vs. Male Sex. (B) Age above vs. below median (88.4 years). (C) Present vs. absent Alzheimer's Disease based on NIA-Reagan Criteria (intermediate/high = present; low/no = absent). (D) High vs. low actigraphic rhythmicity based on 24-hour activity rhythms determined ante-mortem in a subset of 134 participants by actigraphy and quantified using the interdaily stability metric as described in the text. Female sex, higher age, and absence of dementia were associated with an earlier timing of methylation nadirs.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222754&req=5

pgen-1004792-g006: The effects of sex, age, Alzheimer's disease, and 24-hour activity rhythms on the timing of rhythms of methylation.Circular histograms of the effect of clinical variables on the timing of the nadir of methylation of 21,282 high amplitude DNA methylation sites, in 1 hour bins. P-values determined using Rao's Test for the equality of polar directions. Dark lines indicate angular means. (A) Female vs. Male Sex. (B) Age above vs. below median (88.4 years). (C) Present vs. absent Alzheimer's Disease based on NIA-Reagan Criteria (intermediate/high = present; low/no = absent). (D) High vs. low actigraphic rhythmicity based on 24-hour activity rhythms determined ante-mortem in a subset of 134 participants by actigraphy and quantified using the interdaily stability metric as described in the text. Female sex, higher age, and absence of dementia were associated with an earlier timing of methylation nadirs.
Mentions: A number of clinical factors such as age [12], sex [13], [14], and presence of Alzheimer's disease [15] have been described to impact 24-hour rhythms. Moreover, dorsolateral prefrontal cortex molecular 24-hour rhythms may plausibly reflect or impact observed behavioral 24-hour rhythms. We therefore examined the impact of these factors on the amplitude and timing of 21,282 high amplitude DNA methylation sites (including intergenic sites). We assessed the effect of these variables on the parameters of DNA methylation rhythmicity by considering extended cosine models of the form M = m+(β1+β2x)*cos(t−βA−βBx) [Eq3] where x represents high vs. low age, male vs. female sex, present vs. absent Alzheimer's disease, or high vs. low behavioral rhythmicity, β2 reflects the effect of x on amplitude, and βB reflects the effect of x on phase. Female sex, higher age, and absence of dementia were associated with an earlier average phase of rhythms of methylation (Figure 6) while the presence of Alzheimer's disease, female sex, higher age, and lower ante-mortem actigraphic rhythmicity were associated with a lower average amplitude of methylation rhythms (Figure 7).

Bottom Line: We then related rhythms of DNA methylation with rhythms of RNA expression determined by RNA sequencing.We found evidence of significant 24-hour rhythmicity of DNA methylation.Regions near transcription start sites were enriched for high-amplitude rhythmic DNA methylation sites, which were in turn time locked to 24-hour rhythms of RNA expression of nearby genes, with the nadir of methylation preceding peak transcript expression by 1-3 hours.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
Circadian rhythms modulate the biology of many human tissues, including brain tissues, and are driven by a near 24-hour transcriptional feedback loop. These rhythms are paralleled by 24-hour rhythms of large portions of the transcriptome. The role of dynamic DNA methylation in influencing these rhythms is uncertain. While recent work in Neurospora suggests that dynamic site-specific circadian rhythms of DNA methylation may play a role in modulating the fungal molecular clock, such rhythms and their relationship to RNA expression have not, to our knowledge, been elucidated in mammalian tissues, including human brain tissues. We hypothesized that 24-hour rhythms of DNA methylation exist in the human brain, and play a role in driving 24-hour rhythms of RNA expression. We analyzed DNA methylation levels in post-mortem human dorsolateral prefrontal cortex samples from 738 subjects. We assessed for 24-hour rhythmicity of 420,132 DNA methylation sites throughout the genome by considering methylation levels as a function of clock time of death and parameterizing these data using cosine functions. We determined global statistical significance by permutation. We then related rhythms of DNA methylation with rhythms of RNA expression determined by RNA sequencing. We found evidence of significant 24-hour rhythmicity of DNA methylation. Regions near transcription start sites were enriched for high-amplitude rhythmic DNA methylation sites, which were in turn time locked to 24-hour rhythms of RNA expression of nearby genes, with the nadir of methylation preceding peak transcript expression by 1-3 hours. Weak ante-mortem rest-activity rhythms were associated with lower amplitude DNA methylation rhythms as were older age and the presence of Alzheimer's disease. These findings support the hypothesis that 24-hour rhythms of DNA methylation, particularly near transcription start sites, may play a role in driving 24-hour rhythms of gene expression in the human dorsolateral prefrontal cortex, and may be affected by age and Alzheimer's disease.

Show MeSH
Related in: MedlinePlus