Dissecting bipolar disorder complexity through epigenomic approach

Ludwig, Birgit; Dwivedi, Yogesh K.

doi:10.1038/mp.2016.123

Cited by 65 publications

(39 citation statements)

References 141 publications

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“…Using gene-set enrichment analysis (GSEA) we identified enrichment in histone H3-K4 demethylation: the expression levels of genes associated with this GO term were upregulated in BPD brains compared to controls. Numerous studies indicate that histone modifications have important roles in BPD 46 . One of the best characterized histone modifications is H3-K4 methylation, an epigenetic phenomenon highly enriched at transcriptional start sites (TSS) and associated with active transcription.…”

Section: Discussionmentioning

confidence: 99%

Coding and non-coding RNA dysregulation in bipolar disorder

Luykx¹,

Giuliani²,

Giuliani³

et al. 2018

Preprint

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office 4.127 (Stratenum), HP 4.205 | 3584 CG Utrecht | The Netherlands | +31 (0)88 75 68638 | j.luykx@umcutrecht.nl Word count abstract: 192 Word count manuscript: 3146 Number of figures: 3 Number of tables: 1 Running title: Coding and non-coding RNAs in bipolar disorder. AbstractThe molecular mechanisms underlying bipolar disorder (BPD) have remained largely unknown. Postmortem brain tissue studies comparing BPD patients with healthy controls have produced a heterogeneous array of potentially implicated protein-coding RNAs. We hypothesized that dysregulation of not only coding, but multiple classes of RNA (coding RNA, long non-coding (lnc) RNA, circular (circ) RNA, and/or alternative splicing) underlie the pathogenesis of BPD. Using nonpolyadenylated libraries we performed RNA sequencing in postmortem human medial frontal gyrus tissue from BPD patients and healthy controls. We found twenty genes, some of which not previously implicated in BPD, differentially expressed. PCR validation and replication confirmed the implication of these DE genes. Functional analyses identified enrichment of angiogenesis, vascular system development and histone H3-K4 demethylation. In addition, ten lncRNA transcripts were differentially expressed. Furthermore, we detected an overall increased number of alternative splicing events in BPD, as well as an increase in the number of genes carrying alternative splicing events. Finally, we report altered levels of two circular transcripts, cNEBL and cEPHA3. In conclusion, our non-coding RNA findings demonstrate that RNA dysregulation in BPD is not limited to coding regions, opening avenues for future pharmacological investigations and biomarker research.

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Section: Discussionmentioning

confidence: 99%

Coding and non-coding RNA dysregulation in bipolar disorder

Luykx¹,

Giuliani²,

Giuliani³

et al. 2018

Preprint

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“…The recent advancement in epigenome‐wide analyses has advanced the field beyond a gene‐candidate approach towards a more comprehensive mapping of the neuroepigenome. In this regard, life exposure‐ and phenotype‐specific epigenome signatures are constantly being generated, as in the case of childhood maltreatment, MDD, BD, SCZ, autism spectrum disorder, eating disorders and shared features, such as suicidality or psychosis . These epigenomic studies have uncovered dysregulation of multiple biological pathways, including the previously identified HPA, monoaminergic, and neurotrophin systems.…”

Section: Potential Use Of Epigenetics For Mechanistic Insight and Novmentioning

confidence: 99%

“…In this regard, life exposure-and phenotype-specific epigenome signatures are constantly being generated, as in the case of childhood maltreatment, 33 MDD, 34 BD, 35 SCZ, 36 autism spectrum disorder, 37,38 eating disorders 39 and shared features, such as suicidality 31 or psychosis. 40,41 These epigenomic studies have uncovered dysregulation of multiple biological pathways, including the previously identified HPA, monoaminergic, and neurotrophin systems. In addition to these classical pathways, epigenetic alteration of the glutamatergic, GABAergic, Reelin, and polyamine systems, among others, have been detected in brains from affected individuals.…”

Section: Epigenetic Programming Of Neuropsychiatric Systems By Adversmentioning

confidence: 99%

Epigenetics applied to psychiatry: Clinical opportunities and future challenges

Kular

2018

Psychiatry Clin Neurosci

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Psychiatric disorders are clinically heterogeneous and debilitating chronic diseases resulting from a complex interplay between gene variants and environmental factors. Epigenetic processes, such as DNA methylation and histone posttranslational modifications, instruct the cell/tissue to correctly interpret external signals and adjust its functions accordingly. Given that epigenetic modifications are sensitive to environment, stable, and reversible, epigenetic studies in psychiatry could represent a promising approach to better understanding and treating disease. In the present review, we aim to discuss the clinical opportunities and challenges arising from the epigenetic research in psychiatry. Using selected examples, we first recapitulate key findings supporting the role of adverse life events, alone or in combination with genetic risk, in epigenetic programming of neuropsychiatric systems. Epigenetic studies further report encouraging findings about the use of methylation changes as diagnostic markers of disease phenotype and predictive tools of progression and response to treatment. Then we discuss the potential of using targeted epigenetic pharmacotherapy, combined with psychosocial interventions, for future personalized medicine for patients. Finally, we review the methodological limitations that could hinder interpretation of epigenetic data in psychiatry. They mainly arise from heterogeneity at the individual and tissue level and require future strategies in order to reinforce the biological relevance of epigenetic data and its translational use in psychiatry. Overall, we suggest that epigenetics could provide new insights into a more comprehensive interpretation of mental illness and might eventually improve the nosology, treatment, and prevention of psychiatric disorders.

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“…Thus, BD is a complex condition with multiple contributing factors triggered by the interplay of numerous susceptibility genes with many environmental factors (Uher, 2014; Ludwig and Dwivedi, 2016). …”

Section: Introductionmentioning

confidence: 99%

Regulation of gene transcription in bipolar disorders: Role of DNA methylation in the relationship between prodynorphin and brain derived neurotrophic factor

Palazzo

Benatti

Grancini

et al. 2018

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Bipolar Disorder (BD) is a prevalent and disabling condition, determined by gene-environment interactions, possibly mediated by epigenetic mechanisms. The present study aimed at investigating the transcriptional regulation of BD selected target genes by DNA methylation in peripheral blood mononuclear cells of patients with a DSM-5 diagnosis of type I (BD-I) and type II (BD-II) Bipolar Disorders (n = 99), as well as of healthy controls (CT, n = 42). The analysis of gene expression revealed prodynorphin (PDYN) mRNA levels significantly reduced in subjects with BD-II but not in those with BD-I, when compared to CT. Other target genes (i.e. catechol-O-methyltransferase (COMT), glutamate decarboxylase (GAD67), serotonin transporter (SERT) mRNA levels remained unaltered. Consistently, an increase in DNA methylation at PDYN gene promoter was observed in BD-II patients vs CT. After stratifying data on the basis of pharmacotherapy, patients on mood-stabilizers (i.e., lithium and anticonvulsants) were found to have lower DNA methylation at PDYN gene promoter. A significantly positive correlation in promoter DNA methylation was observed in all subjects between PDYN and brain derived neurotrophic factor (BDNF), whose methylation status had been previously found altered in BD. Moreover, among key genes relevant for DNA methylation establishment here analysed, an up-regulation of DNA Methyl Transferases 3b (DNMT3b) and of the methyl binding protein MeCP2 (methyl CpG binding protein 2) mRNA levels was also observed again just in BD-II subjects. A clear selective role of DNA methylation involvement in BD-II is shown here, further supporting a role for BDNF and its possible interaction with PDYN. These data might be relevant in the pathophysiology of BD, both in relation to BDNF and for the improvement of available treatments and development of novel ones that modulate epigenetic signatures.

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Dissecting bipolar disorder complexity through epigenomic approach

Cited by 65 publications

References 141 publications

Coding and non-coding RNA dysregulation in bipolar disorder

Coding and non-coding RNA dysregulation in bipolar disorder

Epigenetics applied to psychiatry: Clinical opportunities and future challenges

Regulation of gene transcription in bipolar disorders: Role of DNA methylation in the relationship between prodynorphin and brain derived neurotrophic factor

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