Genome-wide DNA methylome reveals the dysfunction of intronic microRNAs in major psychosis

Zhao, Hongying; Xu, Jiu Hua; Pang, Lin; Zhang, Yunpeng; Fan, Huihui; Liu, Ling; Liu, Tingting; Yu, Fulong; Zhang, Guanxiong; Lan, Yujia; Bai, Jing; Li, Xia; Xiao, Yun

doi:10.1186/s12920-015-0139-4

Cited by 29 publications

(20 citation statements)

References 57 publications

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“…Interestingly, in the frontal cortex and anterior cingulate, only a few differentially methylated regions overlapped with promoters, whereas a greater proportion occurred in introns and intergenic regions (Xiao et al, 2014). A similar pattern was found in another study, where a high percent of DMRs was found in introns and repeat elements (Zhao et al, 2015) in the brain region BA9. In this particular study, hypermethylated DMRs significantly overlapped with long intergenic non-coding RNAs (lincRNAs), while hypomethylated DMRs significantly overlapped with introns, as well as with short and long interspersed nuclear elements.…”

Section: Dna Methylation In Bdsupporting

confidence: 89%

“…Genome-wide methylation differences have also been analyzed in blood (Dempster et al, 2011; Houtepen et al, 2016; Li et al, 2015; Sabunciyan et al, 2015; Walker et al, 2016) and in different post-mortem brain regions, such as the BA9 (Zhao et al, 2015), frontal cortex (Mill et al, 2008; Xiao et al, 2014), anterior cingulate (Xiao et al, 2014), and cerebellum (Chen et al, 2014) from BD patients and controls.…”

Section: Dna Methylation In Bdmentioning

confidence: 99%

“…In this particular study, hypermethylated DMRs significantly overlapped with long intergenic non-coding RNAs (lincRNAs), while hypomethylated DMRs significantly overlapped with introns, as well as with short and long interspersed nuclear elements. Interestingly, many of the intronic DMRs overlapped with microRNAs, suggesting a role for them in DMR-induced gene expression changes in the BA9 region of patients of BD (Zhao et al, 2015). By using different datasets, a highly significant correlation between methylation and gene expression has been reported in the cerebellum, as well (Chen et al, 2014).…”

Section: Dna Methylation In Bdmentioning

confidence: 99%

“…Specifically, the inconsistencies are coming not only from the different tissues analyzed (blood, prefrontal cortex, anterior cingulate, cerebellum, and sperm), but also due to methodological variations in the studies: three studies have used methylated DNA immunoprecipitation (MeDIP-seq) followed by next generation sequencing (Li et al, 2015; Xiao et al, 2014; Zhao et al, 2015), two studies have used the Illumina Infinium HumanMethylation27 beadchip (Chen et al, 2014; Dempster et al, 2011), three studies have used the Illumina Infinium HumanMethylation450 beadchip (Houtepen et al, 2016; Sabunciyan et al, 2015; Walker et al, 2016), and one used CpG-island microarrays (Mill et al, 2008) for the assessment of methylation changes. Of note, even though MeDIP-seq and microarray-based analyses have been shown to present a good positive correlation, MeDIP-seq allows a wider interrogation of methylation regions of the genome, including thousands of non-RefSeq genes and repetitive elements that are not assessed in microarrays (Clark et al, 2012).…”

Section: Dna Methylation In Bdmentioning

confidence: 99%

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The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

Fries

McAlpin

et al. 2016

Neuroscience & Biobehavioral Reviews

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Bipolar disorder (BD) is a multifactorial illness thought to result from an interaction between genetic susceptibility and environmental stimuli. Epigenetic mechanisms, including DNA methylation, can modulate gene expression in response to the environment, and therefore might account for part of the heritability reported for BD. This paper aims to review evidence of the potential role of DNA methylation in the pathophysiology and treatment of BD. In summary, several studies suggest that alterations in DNA methylation may play an important role in the dysregulation of gene expression in BD, and some actually suggest their potential use as biomarkers to improve diagnosis, prognosis, and assessment of response to treatment. This is also supported by reports of alterations in the levels of DNA methyltransferases in patients and in the mechanism of action of classical mood stabilizers. In this sense, targeting specific alterations in DNA methylation represents exciting new treatment possibilities for BD, and the ‘plastic’ characteristic of DNA methylation accounts for a promising possibility of restoring environment-induced modifications in patients.

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Section: Dna Methylation In Bdsupporting

confidence: 89%

Section: Dna Methylation In Bdmentioning

confidence: 99%

Section: Dna Methylation In Bdmentioning

confidence: 99%

Section: Dna Methylation In Bdmentioning

confidence: 99%

See 2 more Smart Citations

The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

Fries

McAlpin

et al. 2016

Neuroscience & Biobehavioral Reviews

View full text Add to dashboard Cite

show abstract

“…DNA methylation difference of human leukocyte antigen (HLA) complex group 9 gene (HCG9) 90 was replicated in an independent sample set. 91 Other studies showed altered methylation statuses of drebrin-like protein, 88 PIK3R1, BTN3A3, NHLH1, SLC16A7, 92 MSX1, CCND2, DAXX, 93 and hsa-mir-7-3, 94 though the findings are not consistent across studies. When the bulk brain is homogenized and methylation analysis is performed, the obtained results almost reflect the DNA methylation levels of glial cells.…”

Section: Epigenomementioning

confidence: 95%

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

Kato

2019

Psychiatry Clin Neurosci

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Biological studies of bipolar disorder initially focused on the mechanism of action for antidepressants and antipsychotic drugs, and the roles of monoamines (e.g., serotonin, dopamine) have been extensively studied. Thereafter, based on the mechanism of action of lithium, intracellular signal transduction systems, including inositol metabolism and intracellular calcium signaling, have drawn attention. Involvement of intracellular calcium signaling has been supported by genetics and cellular studies. Elucidation of the neural circuits affected by calcium signaling abnormalities is critical, and our previous study suggested a role of the paraventricular thalamic nucleus. The genetic vulnerability of mitochondria causes calcium dysregulation and results in the hyperexcitability of serotonergic neurons, which are suggested to be susceptible to oxidative stress. Efficacy of anticonvulsants, animal studies of candidate genes, and studies using induced pluripotent stem cell‐derived neurons have suggested a relation between bipolar disorder and the hyperexcitability of neurons. Recent genetic findings suggest the roles of polyunsaturated acids. At the systems level, social rhythm therapy targets circadian rhythm abnormalities, and cognitive behavioral therapy may target emotion/cognition (E/C) imbalance. In the future, pharmacological and psychosocial treatments may be combined and optimized based on the biological basis of each patient, which will realize individualized treatment.

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Differentially methylated regions in bipolar disorder and suicide

Gaine

Seifuddin²,

Sabunciyan³

et al. 2019

American J of Med Genetics Pt B

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The addition of a methyl group to, typically, a cytosine-guanine dinucleotide (CpG) creates distinct DNA methylation patterns across the genome that can regulate gene expression. Aberrant DNA methylation of CpG sites has been associated with many psychiatric disorders including bipolar disorder (BD) and suicide. Using the Sur-eSelect XT system, Methyl-Seq, we investigated the DNA methylation status of CpG sites throughout the genome in 50 BD individuals (23 subjects who died by suicide and 27 subjects who died from other causes) and 31 nonpsychiatric controls. We identified differentially methylated regions (DMRs) from three analyses: (a) BD subjects compared to nonpsychiatric controls (BD-NC), (b) BD subjects who died by suicide compared to nonpsychiatric controls (BDS-NC), and (c) BDS subjects compared to BD subjects who died from other causes (BDS-BDNS). One DMR from the BDS-NC analysis, located in ARHGEF38, was significantly hypomethylated (23.4%) in BDS subjects. This finding remained significant after multiple testing (P Bootstrapped = 9.0 × 10 −3 ), was validated using pyrosequencing, and was more significant in males. A secondary analysis utilized Ingenuity Pathway Analysis to identify enrichment in nominally significant DMRs. This identified an association with several pathways including axonal guidance signaling, calcium signaling, β-adrenergic signaling, and opioid signaling. Our comprehensive study provides further support that DNA methylation alterations influence the risk for BD and suicide. However, further investigation is required to confirm these associations and identify their functional consequences. K E Y W O R D SARHGEF38, opioid signaling, suicidal behavior, β-adrenergic signaling

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Genome-wide DNA methylome reveals the dysfunction of intronic microRNAs in major psychosis

Cited by 29 publications

References 57 publications

The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

Differentially methylated regions in bipolar disorder and suicide

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