Hypomethylation of LINE-1 elements in schizophrenia and bipolar disorder

Li, Shufen; Yang, Qiong; Hou, Yu; Jiang, Tian; Zong, Lu; Wang, Zhongju; Luo, Xia; Liang, Wenying; Zhao, Hu; Ning, Yuping; Zhao, Chen

doi:10.1016/j.jpsychires.2018.10.009

Cited by 47 publications

(32 citation statements)

References 19 publications

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“…Regarding the innate LTR expression within dnmt1 +/+ RSCs, in conjunction with previous reports of inherent RE activity within human neural tissue, it is worth considering how RE activity may contribute to neural stem cell biology. It is well known that dysregulation of REs is a hallmark of many human neurodegenerative diseases 67,[79][80][81][82] . Future evaluations regarding the innate cost-to-benefit ratio of RE activity could provide crucial evidence for the development of neurodegenerative therapies.…”

Section: Discussionmentioning

confidence: 99%

dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

Angileri

Gross

2020

Preprint

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The ciliary marginal zone (CMZ) of the zebrafish retina contains a population of actively proliferating resident stem cells, which generate retinal neurons throughout life. The maintenance methyltransferase, dnmt1, is expressed within the CMZ. Loss of dnmt1 function results in gene misregulation and cell death in a variety of developmental contexts, however, its role in retinal stem cell (RSC) maintenance is currently unknown. Here, we demonstrate that zebrafish dnmt1 s872 mutants possess severe defects in RSC maintenance within the CMZ. Using a combination of immunohistochemistry, in situ hybridization, and a transgenic reporter assay, our results demonstrate a requirement for dnmt1 activity in the regulation of RSC proliferation, gene expression and in the repression of endogenous retroelements (REs). Ultimately, cell death is elevated in the dnmt1 -/-CMZ, but in a p53-independent manner. Using a transgenic reporter for RE transposition activity, we demonstrate increased transposition in the dnmt1 -/-CMZ. Taken together our data identify a critical role for dnmt1 function in RSC maintenance in the vertebrate eye. Introduction:The distal region of the vertebrate retina, termed the ciliary marginal zone (CMZ), contains a population of resident retinal stem cells (RSCs). The CMZ remains proliferative throughout the life of fish, but it proliferates to a more limited extent during the lifetime of amphibians and birds 1-6 . Whether an analogous structure exists in mammals is debated, but there are distinct, progenitor-like cells in the periphery of the retina that are active during embryogenesis 7-9 . Mammalian RSCs can also be isolated from the adult ciliary margin, cultured in vitro, and stimulated to produce retinal neurons 10-13 .However, this activity has not been demonstrated in the mature mammalian retinae in vivo.Studies of the CMZ have primarily focused on zebrafish and Xenopus models to determine genetic pathways required for RSC identity 2,14-16 and to characterize the epigenetic networks which regulate RSC function 17,18 . By comparison, the mechanisms mediating RSC maintenance in vivo remain unknown. In studies of RSCs, the zebrafish has been advantageous given that it possesses a highly active RSC population and is tractable for genetic and pharmacological manipulations, transgenesis and in vivo imaging 19,20 .DNA methylation, a frequently studied epigenetic modification, is the process through which a methyl group is added to the fifth carbon of cytosine nucleotides and is commonly found at CpG dinucleotide sequences 21 . Members of the family of DNA methyltransferase (Dnmt) enzymes 22,23 catalyze this epigenetic modification. Dnmt1 serves as a maintenance methyltransferase, copying the methylation pattern from parent to daughter strand during DNA replication and its function is required for cell cycle progression [24][25][26] . Loss of Dnmt1 function results in genomic hypomethylation 27-29 and in developmental contexts and specific organ systems, this often compromises progenitor cell maintenance 24...

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Section: Discussionmentioning

confidence: 99%

dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

Angileri

Gross

2020

Preprint

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“…Lower global methylation in patients treated with AAPs was observed in three studies although the comparator groups in each study differed. Increased global methylation was observed in three studies and one study identified increases in responders only . One study did not identify an effect of antipsychotic dose on global methylation levels …”

Section: Resultsmentioning

confidence: 94%

“…Our systematic review yielded 29 studies (Table 1). Eighteen studies analyzed methylation in patients with schizophrenia, four studies in patients with bipolar disorder, and seven studies in a combined sample of patients with schizophrenia and bipolar disorder. The majority (n=22) of studies included observational sampling, such as cross‐sectional or case‐control studies, and the remaining analyzed changes in a prospective manner.…”

Section: Resultsmentioning

confidence: 99%

“…The most commonly employed measurement utilized restriction enzymes (five studies) followed by transposable elements (two studies) and ELISA (one study). 26 Obs 133 SCZ AAP and TAP Blood Global Cheng et al 27 Obs and prosp 30 Obs 172 BD olanzapine and quetiapine Blood d EWAS and genespecific Kinoshita et al 31 Prosp 21 SCZ olanzapine Blood EWAS Li et al 32 Obs 92 SCZ; 99 BD; 92 HC AAP and TAP Blood global Lott et al 33 Obs 85 SCZ NR blood gene-specific Melas et al 34 Obs 177 SCZ; 171 HC AAP and TAP Blood Global and genespecific Mill et al 35 Obs 35 SZ; 35 BD; 35 HC NR Brain EWAS Miura et al 36 Prosp 34 SCZ risperidone Blood Gene-specific Moons et al 37 Obs 438 SCZ AAP and TAP Blood Gene-specific Nour El Huda et al 38 Obs 138 SCZ; 132 HC AAP and TAP Blood Gene-specific Rukova et al 39 Prosp 20 SCZ; 220 HC NR Blood EWAS Shi et al 40 Prosp 288 SCZ risperidone Blood Gene-specific Swathy et al 41 Obs 184 SCZ; 330 HC NR Blood Global Tang et al 42 Prosp 82 SCZ AAP and TAP Blood Gene-specific Venugopal et al 43 Prosp 47 SCZ; 47 HC AAP Blood Gene-specific Zong et al 44 Obs 279 SCZ; 265 HC AAP and TAP Blood Gene-specific Details of 29 studies included in the systematic review including study design, type of antipsychotic within study, sample type for DNA methylation analysis, and overall DNA methylation strategy. AAP = atypical antipsychotic; BD = bipolar disorder; HC = healthy control; MDD = major depressive disorder; NR = not reported; obs = observational; PR = primary relative; pros = prospective; scz = schizophrenia; TAP = typical antipsychotic; UPR = unaffected primary relative.…”

Section: Global Methylation Studiesmentioning

confidence: 99%

“…Increased global methylation was observed in three studies and one study identified increases in responders only. 20,32,41 One study did not identify an effect of antipsychotic dose on global methylation levels. 21…”

Section: Global Methylation Studiesmentioning

confidence: 99%

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Antipsychotic Medications and DNA Methylation in Schizophrenia and Bipolar Disorder: A Systematic Review

et al. 2020

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The pharmacoepigenetics of antipsychotic treatment in severe mental illness is a growing area of research that aims to understand the interface between antipsychotic treatment and genetic regulation. Pharmacoepigenetics may some day assist in identifying treatment response mechanisms or become one of the components in the implementation of precision medicine. To understand the current evidence regarding the effects of antipsychotics on DNA methylation a systematic review with qualitative synthesis was performed through Pubmed, Embase and Psychinfo from earliest data to June 2019. Studies were included if they analyzed DNA methylation in an antipsychotic‐treated population of patients with schizophrenia or bipolar disorder. Data extraction occurred via a standardized format and study quality was assessed. Twenty‐nine studies were identified for inclusion. Study design, antipsychotic type, sample source, and methods of DNA methylation measurement varied across all studies. Eighteen studies analyzed methylation in patients with schizophrenia, four studies in patients with bipolar disorder, and seven studies in a combined sample of schizophrenia and bipolar disorder. Twenty‐two studies used observational samples whereas the remainder used prospectively treated samples. Six studies assessed global methylation, five assessed epigenome‐wide, and 15 performed a candidate epigenetic study. Two studies analyzed both global and gene‐specific methylation, whereas one study performed a simultaneous epigenome‐wide and gene‐specific study. Only three genes were analyzed in more than one gene‐specific study and the findings were discordant. The state of the pharmacoepigenetic literature on antipsychotic use is still in its early stages and uniform reporting of methylation site information is needed. Future work should concentrate on using prospective sampling with appropriate control groups and begin to replicate many of the novel associations that have been reported.

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