Role of CpG context and content in evolutionary signatures of brain DNA methylation

Xin, Yurong; O’Donnell, Anne H.; Ge, Yongchao; Chanrion, Benjamin; Milekic, Maria H.; Rosoklija, Gorazd; Stankov, Aleksandar; Arango, Victoria; Dwork, Andrew J.; Gingrich, Jay A.; Haghighi, Fatemeh

doi:10.4161/epi.6.11.17876

Cited by 32 publications

(16 citation statements)

References 48 publications

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“…DNA methylation patterns are highly conserved in CpG-rich gene promoters of mouse and human brains. 128 This is also the case, for example, for the TSP1 gene promoter involved in angiogenesis after ischemia as described above. 114,116 Histone modifications and especially colocalizing different epigenetic marks are largely preserved between species where transcription factor-binding sites and gene expression are maintained as well.…”

Section: Aspects Of Translationmentioning

confidence: 81%

Epigenetic Mechanisms in Cerebral Ischemia

Schweizer

Meisel

Märschenz

2013

J Cereb Blood Flow Metab

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Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration.

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Section: Aspects Of Translationmentioning

confidence: 81%

Epigenetic Mechanisms in Cerebral Ischemia

Schweizer

Meisel

Märschenz

2013

J Cereb Blood Flow Metab

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“…These findings appear despite the significant evidence of tissue-specific DNA methylation profiles (60–63), leading to the question of how a ‘social adversity-related’ epigenetic signal might appear in cell populations as diverse as peripheral blood cells and CNS-derived cells. One possibility is that social adversity activates stress responses that include signals such as steroid hormones (e.g., glucocorticoids) or cytokines, which act in multiple cell types and might initiate a coordinated remodelling of the epigenome at specific sites.…”

Section: Resultsmentioning

confidence: 99%

Effects of the Social Environment and Stress on Glucocorticoid Receptor Gene Methylation: A Systematic Review

Turecki

Meaney

2016

Biological Psychiatry

629

419

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The early-life social environment can induce stable changes that influence neurodevelopment and mental health. Research focused on early-life adversity revealed that early-life experiences have a persistent impact on gene expression and behaviour through epigenetic mechanisms. The hypothalamus-pituitary-adrenal (HPA) axis is sensitive to changes in the early-life environment that associate with DNA methylation of a neuron-specific exon 17 promoter of the glucocorticoid receptor (GR; NR3C1). Since Weaver et al published the initial findings in 2004, numerous reports have investigated GR gene methylation in relationship to early-life experience, parental stress and psychopathology. We conducted a systematic review of this growing literature, which identified 40 articles (13 animal and 27 human studies) published since 2004. The majority of these examined the GR exon variant 1F in humans or the GR17 in rats, and 89% of human studies and 70% of animal studies of early-life adversity reported increased methylation at this exon variant. All the studies investigating exon 1F/17 methylation in conditions of parental stress (one animal study and 7 human studies) also reported increased methylation. Studies examining psychosocial stress and psychopathology had less consistent results, with 67% of animal studies reporting increased exon 17 methylation and 17% of human studies reporting increased exon 1F methylation. We found great consistency among studies investigating early life adversity and the effect of parental stress, even if the precise phenotype and measures of social environment adversity varied among studies. These results are encouraging and warrant further investigation to better understand correlates and characteristics of these associations.

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“…We found that those CpGs that are more conserved during evolution showed the lowest values of inter-individual methylation variability. Comparing human-mouse methylation, a study showed that methylation correlates, although weakly, with sequence conservation [ 31 ]. Analyzing the relationship between DNA methylation, genetics, and expression in fibroblasts, other authors proved that CpGs with low inter-individual methylation variation showed a good degree of sequence conservation [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation variability among individuals is related to CpGs cluster density and evolutionary signatures

et al. 2018

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BackgroundIn recent years, epigenetics has gained a central role in the understanding of the process of natural selection. It is now clear how environmental impacts on the methylome could promote methylation variability with direct effects on disease etiology as well as phenotypic and genotypic variations in evolutionary processes. To identify possible factors influencing inter-individual methylation variability, we studied methylation values standard deviation of 166 healthy individuals searching for possible associations with genomic features and evolutionary signatures.ResultsWe analyzed methylation variability values in relation to CpG cluster density and we found a strong association between them (p-value < 2.2 × 10− 16). Furthermore, we found that genes related to CpGs with high methylation variability values were enriched for immunological pathways; instead, those associated with low ones were enriched for pathways related to basic cellular functions. Finally, we found an association between methylation variability values and signals of both ancient (p-value < 2.2 × 10− 16) and recent selective pressure (p-value < 1 × 10− 4).ConclusionOur results indicate the presence of an intricate interplay between genetics, epigenetic code and evolutionary constraints in humans.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4618-9) contains supplementary material, which is available to authorized users.

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Role of CpG context and content in evolutionary signatures of brain DNA methylation

Cited by 32 publications

References 48 publications

Epigenetic Mechanisms in Cerebral Ischemia

Epigenetic Mechanisms in Cerebral Ischemia

Effects of the Social Environment and Stress on Glucocorticoid Receptor Gene Methylation: A Systematic Review

DNA Methylation variability among individuals is related to CpGs cluster density and evolutionary signatures

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