Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins

Kuratomi, Go; Iwamoto, Kazuya; Bundo, Miki; Kusumi, Ichiro; Kato, Nobuo; Iwata, Nakao; Ozaki, Norio; Kato, Takeshi

doi:10.1038/sj.mp.4002001

Cited by 177 publications

(109 citation statements)

References 35 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…If retinoids modulate CD38 transcription in the brain, which in turn mediates oxytocin release, then the relationship we have shown [72] between cognitive function and CD38 mRNA levels in LBC cells may be reflecting common state characteristics of OT-CD38-RA pathways in different tissues. Indeed, various studies have employed LBC lines to model brain dysfunctions in autism [90][91][92] and other neuropsychiatric disorders [93][94][95][96][97].…”

Section: Link Between Cd38 Expression and Clinical Characteristics Inmentioning

confidence: 99%

Are retinoids potential therapeutic agents in disorders of social cognition including autism?

et al. 2011

View full text Add to dashboard Cite

Edited by Sergio Papa, Gianfranco Gilardi and Wilhelm JustKeywords: Autism spectrum disorder (ASD) All-trans retinoic acid (ATRA) CD38 Oxytocin Polymorphism a b s t r a c t Increasing evidence suggests that the nonapeptide, oxytocin (OT), helps shape social and affiliative behaviors not only in lower mammals but also in humans. Recently, an essential mediator of brain OT release has been discovered, ADP-ribosyl cyclase and/or CD38. We have subsequently shown that polymorphisms across the CD38 gene are associated with autism spectrum disorders (ASD). Notably, CD38 expression in lymphoblastoid cells (LBC) is reduced in cell lines derived from ASD subjects compared to parental cell lines. Intriguingly, a correlation was observed between CD38 expression and measures of social function in ASD. Finally, we have shown that all-trans retinoic acid (ATRA), a known inducer of CD38 transcription, can rescue low CD38 expressing LBC lines derived from ASD subjects and restore normal levels of transcription of this ectoenzyme providing 'proof of principle' in a peripheral model that retinoids are potential therapeutic agents in ASD. Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. OxytocinClassically, the nonapeptide oxytocin (OT) has been viewed as a hypothalamic neuropeptide that is released into the general circulation from the neural lobe of the pituitary, inducing uterine contractions during parturition and milk ejection during lactation. OT is derived from a pre-prohormone precursor that is synthesized in the hypothalamus and stored in vesicles at the posterior pituitary for storage and subsequent release into the bloodstream (see [1] for comprehensive review of the oxytocin receptor system). OT and social behaviorBeyond the long-known peripheral effects of OT, a wealth of animal studies have elaborated the role of OT, or their analogues such as isotocin and vasotocin [2], in molding social behavior from fish to mammals [3]. In the past few years the role of OT has also been examined in our own species, and similar to what has been learned from animal studies, it appears that this nonapeptides also influence social behaviors in humans [4,5]. Indeed, OT has been suggested as the 'great facilitator of life' in a recent review [6].In humans, intranasal administration of OT has been shown to increase trust [7], facilitate mind-reading [8], enhance human memory for social identity [9], increase positive communication between couples [10], increase gaze to the eye region [11] and increase generosity [12]. Intriguingly, OT plasma levels have been linked to individual patterns of maternal-fetal attachment [13] and salivary OT levels were associated with bonding to own parents and inversely related to psychological distress, particularly depressive symptoms [14]. Social anxiety symptom severity, adjusted for age and gender in a healthy group of subjects, was associated with higher plasma oxytocin levels [15]. Imaging studies reinforce the role of OT in influencing human social ...

show abstract

Section: Link Between Cd38 Expression and Clinical Characteristics Inmentioning

confidence: 99%

Are retinoids potential therapeutic agents in disorders of social cognition including autism?

et al. 2011

View full text Add to dashboard Cite

show abstract

“…The DNA methylation profile is heritable through mitosis, but the fidelity of this transmission is imperfect (Bennett-Baker et al 2003) and may contribute to differences in gene expression and phenotype observed between genetically identical individuals, whether isogenic strains of mice (Gartner and Baunack 1981;Pritchard et al 2006) or human MZ twins (Fraga et al 2005;Martin 2005;Kuratomi et al 2008;Kaminsky et al 2009;Javierre et al 2010).…”

mentioning

confidence: 99%

“…Twin studies, which have traditionally enabled estimation of genetic and environmental components to phenotypic variance, have been used to estimate the effect of these factors on DNA methylation, at both a gene-specific level (Heijmans et al 2007;Wong et al 2010) or throughout the genome (Kuratomi et al 2008;Kaminsky et al 2009;Javierre et al 2010;Rakyan et al 2011a,b). Such studies are improving our understanding of the processes involved in the regulation of epigenetic variation and are disentangling the relative contributions of epigenetics, environment, and genetic variation, together with stochastic factors, in complex traits (Bell and Saffery 2012).…”

mentioning

confidence: 99%

Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence

Gordon¹,

Joo²,

Powell³

et al. 2012

Genome Res.

258

216

View full text Add to dashboard Cite

Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic variability. Using DNA methylation profiling of~20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome.

show abstract

“…However, this method can be used for the analysis of monozygotic twins having the same genomic sequences. Applying this method to a pair of monozygotic twins discordant for bipolar disorder, we isolated ten DNA fragments derived from CpG islands or putative promoters [79]. Among these ten fragments, DNA methylation differences in four regions was confirmed by bisulfite sequencing between the bipolar twin and control co-twin.…”

Section: Dna Methylation Differences Between Discordant Twinsmentioning

confidence: 99%

“…To test the pathophysiological significance of DNA methylation, Kuratomi et al [79] performed a case control analysis using Pyrosequencing and found an altered DNA methylation status of spermine synthase (SMS) in female patients with bipolar disorder. However, DNA methylation had increased in the bipolar patients, while it had decreased in the bipolar twin.…”

Section: Dna Methylation Differences Between Discordant Twinsmentioning

confidence: 99%

Epigenetics in mood disorders

McGowan

Kato

2007

Environ Health Prev Med

View full text Add to dashboard Cite

Depression develops as an interaction between stress and an individual's vulnerability to stress. The effect of early life stress and a gene-environment interaction may play a role in the development of stress vulnerability as a risk factor for depression. The epigenetic regulation of the promoter of the glucocorticoid receptor gene has been suggested as a molecular basis of such stress vulnerability. It has also been suggested that antidepressive treatment, such as antidepressant medication and electroconvulsive therapy, may be mediated by histone modification on the promoter of the brain-derived neurotrophic factor gene. Clinical genetic studies in bipolar disorder suggest the role of genomic imprinting, although no direct molecular evidence of this has been reported. The role of DNA methylation in mood regulation is indicated by the antimanic effect of valproate, a histone deacetylase inhibitor, and the antidepressive effect of S-adenosyl methionine, a methyl donor in DNA methylation. Studies of postmortem brains of patients have implicated altered DNA methylation of the promoter region of membrane-bound catechol-O-methyltransferase in bipolar disorder. An altered DNA methylation status of PPIEL (peptidylprolyl isomerase Elike) was found in a pair of monozygotic twins discordant for bipolar disorder. Hypomethylation of PPIEL was also found in patients with bipolar II disorder in a case control analysis. These fragmentary findings suggest the possible role of epigenetics in mood disorders. Further studies of epigenetics in mood disorders are warranted.

show abstract

Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins

Cited by 177 publications

References 35 publications

Are retinoids potential therapeutic agents in disorders of social cognition including autism?

Are retinoids potential therapeutic agents in disorders of social cognition including autism?

Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence

Epigenetics in mood disorders

Contact Info

Product

Resources

About