An association study of the m6A genes with major depressive disorder in Chinese Han population

Du, Tingfu; Rao, Shuquan; Wu, Lin; Ye, Ning; Liu, Zeyue; Hu, Huiling; Xiu, Jianbo; Shen, Yan; Xu, Qi

doi:10.1016/j.jad.2015.05.025

Cited by 102 publications

(76 citation statements)

References 49 publications

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“…Although details on the relationship between RNA modifications and disease are just beginning to be examined in depth (67), it is worth noting that Gsk-3 is inhibited by the mood-stabilizing drug lithium (9,10). A recent study showed that genes involved in m 6 A modification are associated with major depressive disorder in a Han Chinese population (68). The data presented here raise the possibility that toggling the levels of methylated adenosine on mRNA in the brain could play a role in mood stabilization.…”

Section: Discussionmentioning

confidence: 99%

Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells

Faulds

Egelston

Sedivy

et al. 2018

Journal of Biological Chemistry

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Glycogen synthase kinase-3 (Gsk-3) activity regulates multiple signal transduction pathways, and is also a key component of the network responsible for maintaining stem cell pluripotency. Genetic deletion of Gsk-3α and Gsk-3β or inhibition of Gsk-3 activity via small molecules promotes stem cell pluripotency, yet the mechanism underlying the role for Gsk-3 in this process remains ambiguous. Another cellular process that has been shown to affect stem cell pluripotency is mRNA methylation (m 6 A). Here, we describe an intersection between these components -the regulation of m 6 A by Gsk-3. We find that protein levels for the RNA demethylase, FTO (fat mass and obesity-associated protein), are elevated in Gsk-3α;Gsk-3β-deficient mouse embryonic stem cells (ESCs). FTO is normally phosphorylated by Gsk-3, and mass spectrometry identified the sites on FTO that are phosphorylated in a Gsk-3-dependent fashion. Gsk-3 phosphorylation of FTO leads to polyubiquitination, but in Gsk-3 knockout ESCs, that process is impaired, resulting in elevated levels of FTO protein. As a consequence of altered FTO protein levels, mRNAs in Gsk-3 knockout ESCs have 50% less m 6 A than wild-type ESCs, and m 6 A-seq analysis reveals the specific mRNAs that have reduced m 6 A modifications. Taken together, we provide the first evidence for how m 6 A demethylation is regulated in mammalian cells, and sheds light onto a possible novel mechanism by which Gsk-3 activity regulates stem cell pluripotency.Glycogen synthase kinase-3 (Gsk-3) activity is an important regulator of numerous signal transduction pathways (1). Gsk-3 activity is the sum of two largely redundant proteins, Gsk-3α and Gsk-3β, and in general, Gsk-3 is a negative regulator of cellular signaling (2). Rare among kinases, Gsk-3 is active at a basal state, while pathway activation from upstream signaling cascades results in the inhibition of Gsk-3 activity (2). Gsk-3α and Gsk-3β together regulate signal transduction pathways such as Wnt, protein kinase A (PKA), Hedgehog, transforming growth factor-β (TGF-β), nuclear factor of activated T-cells (NF-AT) and phosphatidylinositol 3-kinase (PI3K)-dependent insulin signaling in a variety of biological settings (3)(4)(5).Gsk-3 activity can be inhibited through the use of small molecule inhibitors, such as SB- (6)(7)(8), and the clinically relevant mood-stabilizer lithium (9,10); however, a drawback to the use of small molecules to study Gsk-3 function is the potential for off-target effects (11). Cells in which Gsk-3α and Gsk-3β have been genetically deleted allows for a more confident assessment of Gsk-3-specific functions. Therefore, we utilize mouse embryonic stem cells (ESCs) deficient in both Gsk-3α and Gsk-3β (Gsk-3α -/-; Gsk-3β -/-), i.e., Gsk-3 double knockout (DKO), to assess Gsk-3-specific functions (12,13). One prominent phenotype of Gsk-3 DKO ESCs is their persistent pluripotency, assessed by their inability to differentiate into all three germs layers in a teratoma assay, as well as by analysis of global gene expression ...

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Section: Discussionmentioning

confidence: 99%

Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells

Faulds

Egelston

Sedivy

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

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“…Deletion of the FTO gene in mice, which is one of the two enzymes responsible for reversing or "erasing" m 6 A modifications (Zhao et al 2016), results in an impairment of dopamine receptor control of neuronal activity and behavioral responses (Hess et al 2013). ALKBH5, also responsible for m 6 A demethylation, has been linked to major depressive disorders (Du et al 2015), suggesting that m 6 A may be playing an important regulatory role in the function of the mammalian brain. A-to-I editing defects have also been associated with neurological diseases (Hideyama and Kwak 2011;Hideyama et al 2012;Gaisler-Salomon et al 2014;Tomaselli et al 2015), such as amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease (Hideyama and Kwak 2011;Hideyama et al 2012).…”

Section: Neurological Diseasesmentioning

confidence: 99%

The RNA modification landscape in human disease

Jonkhout

Tran

Smith

et al. 2017

RNA

490

420

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RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps.

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“…It causes disability and interfering with the ability to eat, sleep, study and work (Dempster et al, 2014;Du et al, 2015). Selective serotonin reuptake inhibitors (SSRI), the first choice for the treatment of depression, act by inhibiting the presynaptic reuptake of serotonin thus increasing the free serotonin available to bind to postsynaptic receptors (Preskorn, 1997;Ban, 2001).…”

Section: Introductionmentioning

confidence: 99%

Transdermal agomelatine microemulsion gel: pyramidal screening, statistical optimization and in vivo bioavailability

et al. 2017

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Agomelatine is a new antidepressant having very low oral drug bioavailability less than 5% due to being liable to extensive hepatic 1st pass effect. This study aimed to deliver agomelatine by transdermal route through formulation and optimization of microemulsion gel. Pyramidal screening was performed to select the most suitable ingredients combinations and then, the design expert software was utilized to optimize the microemulsion formulations. The independent variables of the employed mixture design were the percentages of capryol 90 as an oily phase (X 1 ), Cremophor RH40 and Transcutol HP in a ratio of (1:2) as surfactant/cosurfactant mixture 'S mix ' (X 2 ) and water (X 3 ). The dependent variables were globule size, optical clarity, cumulative amount permeated after 1 and 24 h, respectively (Q1 and Q 24 ) and enhancement ratio (ER). The optimized formula was composed of 5% oil, 45% S mix and 50% water. The optimized microemulsion formula was converted into carbopol-based gel to improve its retention on the skin. It enhanced the drug permeation through rat skin with an enhancement ratio of 37.30 when compared to the drug hydrogel. The optimum ME gel formula was found to have significantly higher C max , AUC 0-24 h and AUC 0-1 than that of the reference agomelatine hydrogel and oral solution. This could reveal the prosperity of the optimized microemulsion gel formula to augment the transdermal bioavailability of agomelatine. ARTICLE HISTORY

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An association study of the m6A genes with major depressive disorder in Chinese Han population

Cited by 102 publications

References 49 publications

Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells

Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells

The RNA modification landscape in human disease

Transdermal agomelatine microemulsion gel: pyramidal screening, statistical optimization and in vivo bioavailability

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