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RNA-seq and miRNA-seq data from pharmacological inhibition of the G9a/GLP histone methyltransferase complex with UNC0642 in SAMP8 mice.

ABSTRACT: Growing evidence demonstrates the epigenetic modulation as a key event in Alzheimer's disease (AD) pathology. Furthermore, recent data suggests that the epigenetic regulation by the methyltransferase G9a is a crucial mechanism involved in learning and memory formation. Taking this into account, we hereby provide genomics data from pharmacological intervention with UNC0642, a potent and selective G9a/GLP in SAMP8 mice, a model of Alzheimer's disease (AD). We have generated novel RNA-seq and miRNA-seq data for three groups, healthy SAMR1, SAMP8 control and SAMP8 treated with UNC0642 (5 mg/Kg). Thus, the new data can be used to find miRNA regulation, and the mRNA's modified in AD under G9a/GLP inhibition.

SUBMITTER: Pawar S

PROVIDER: S-EPMC8257974 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Inhibition of the G9a/GLP histone methyltransferase complex modulates anxiety-related behavior in mice.

Project description:Epigenetic gene-regulation abnormalities have been implicated in various neuropsychiatric disorders including schizophrenia and depression, as well as in the regulation of mood and anxiety. In addition, epigenetic mechanisms are involved in the actions of psychiatric drugs. Current anxiolytic drugs have significant shortcomings, and development of new medications is warranted. Two proteins, G9a (also known as EHMT2 or KMT1C) and GLP (G9a-like protein, also known as EHMT1 or KMT1D), which methylate lysine 9 of histone H3 (H3K9), could be promising anxiolytic targets. Postnatal genetic knock-out of G9a reduces anxiety-related behavior, consistent with the reduction of G9a levels by some medications used to treat anxiety (amitriptyline, imipramine and paroxetine). Conversely, there is increased anxiety-like behavior in mice with GLP haplodeficiency. We sought to determine whether two pharmacological inhibitors of G9a/GLP, UNC0642 and A-366, would have similar effects to genetic G9a/GLP insufficiency. We found that G9a/GLP inhibition with either compound reduced anxiety-like behaviors when administered to adult mice, in conjunction with decreased H3K9 methylation in the brain. In contrast, exposure to these compounds from embryonic day 9.5 (E9.5) until birth increased anxiety-like behaviors and decreased social interaction in adulthood, while H3K9 methylation was at normal levels in the brains of the adult mice. These findings reinforce genetic evidence that G9a/GLP has different effects on anxiety-like behavior at different stages of brain development, and suggest that targeting this histone methyltransferase pathway could be useful for developing new anxiolytic drugs. These data also suggest that antidepressant exposure in utero could have negative effects in adulthood, and further investigation of these effects is warranted.

| S-EPMC5943902 | biostudies-literature

miRNA-seq data from pharmacological inhibition of the G9a histone methyltransferase with UNC0642 in SAMP8 mice

Project description:Purpose: The aim of this study is to compare brain transcriptome profile (RNA-seq) after G9a inhibition. Methods: Hippocampus profiles of 7-month-old SAMP8 Control and SAMP8 Treated mice groups were generated by deep sequencing, pooled using Ilumnia Hiseq. Results: G9a inhibition with UNC0642 induces a transcriptional profile that allows beneficial effects on cognitive performance. Differential expression analysis identified 697 differentially expressed genes (DEG) (fold change cutoff of ≥1.3, p-value<0.05). Of which 217 are reduced, and 480 are increased in SAMP8 UNC0642. Conclusions: Our study showed the first transcriptome analysis of whole brain after G9a inhibition, generated by RNA-seq technology, demonstrating transcriptomic changes.

2021-11-24 | GSE189248 | GEO

miRNA-seq and RNA-seq data from pharmacological inhibition of the G9a histone methyltransferase with UNC0642 in SAMP8 mice

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-11-24 | GSE189250 | GEO

RNA-seq data from pharmacological inhibition of the G9a histone methyltransferase with UNC0642 in SAMP8 mice

2021-11-24 | GSE189249 | GEO

miRNA-seq data from pharmacological inhibition of the G9a histone methyltransferase with UNC0642 in SAMP8 mice

Project description:miRNA-seq data from pharmacological inhibition of the G9a histone methyltransferase with UNC0642 in SAMP8 mice

| PRJNA782199 | ENA

H3K9 methyltransferase G9a and the related molecule GLP.

Project description:The discovery of Suv39h1, the first SET domain-containing histone lysine methyltransferase (HKMT), was reported in 2000. Since then, research on histone methylation has progressed rapidly. Among the identified HKMTs in mammals, G9a and GLP are the primary enzymes for mono- and dimethylation at Lys 9 of histone H3 (H3K9me1 and H3K9me2), and exist predominantly as a G9a-GLP heteromeric complex that appears to be a functional H3K9 methyltransferase in vivo. Recently, many important studies have reported that G9a and GLP play critical roles in various biological processes. The physiological relevance of G9a/GLP-mediated epigenetic gene regulation is discussed.

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miRNA-seq and RNA-seq data from pharmacological inhibition of the G9a histone methyltransferase with UNC0642 in SAMP8 mice

Project description:miRNA-seq and RNA-seq data from pharmacological inhibition of the G9a histone methyltransferase with UNC0642 in SAMP8 mice

| PRJNA782198 | ENA

RNA-seq data from pharmacological inhibition of the G9a histone methyltransferase with UNC0642 in SAMP8 mice

Project description:RNA-seq data from pharmacological inhibition of the G9a histone methyltransferase with UNC0642 in SAMP8 mice

| PRJNA782200 | ENA

The Histone Methyltransferase Inhibitor A-366 Uncovers a Role for G9a/GLP in the Epigenetics of Leukemia.

Project description:Histone methyltransferases are epigenetic regulators that modify key lysine and arginine residues on histones and are believed to play an important role in cancer development and maintenance. These epigenetic modifications are potentially reversible and as a result this class of enzymes has drawn great interest as potential therapeutic targets of small molecule inhibitors. Previous studies have suggested that the histone lysine methyltransferase G9a (EHMT2) is required to perpetuate malignant phenotypes through multiple mechanisms in a variety of cancer types. To further elucidate the enzymatic role of G9a in cancer, we describe herein the biological activities of a novel peptide-competitive histone methyltransferase inhibitor, A-366, that selectively inhibits G9a and the closely related GLP (EHMT1), but not other histone methyltransferases. A-366 has significantly less cytotoxic effects on the growth of tumor cell lines compared to other known G9a/GLP small molecule inhibitors despite equivalent cellular activity on methylation of H3K9me2. Additionally, the selectivity profile of A-366 has aided in the discovery of a potentially important role for G9a/GLP in maintenance of leukemia. Treatment of various leukemia cell lines in vitro resulted in marked differentiation and morphological changes of these tumor cell lines. Furthermore, treatment of a flank xenograft leukemia model with A-366 resulted in growth inhibition in vivo consistent with the profile of H3K9me2 reduction observed. In summary, A-366 is a novel and highly selective inhibitor of G9a/GLP that has enabled the discovery of a role for G9a/GLP enzymatic activity in the growth and differentiation status of leukemia cells.

| S-EPMC4492996 | biostudies-literature

MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a.

Project description:DNA CpG methylation and histone H3 lysine 9 (H3K9) methylation are two major repressive epigenetic modifications, and these methylations are positively correlated with one another in chromatin. Here we show that G9a or G9a-like protein (GLP) dimethylate the amino-terminal lysine 44 (K44) of mouse Dnmt3a (equivalent to K47 of human DNMT3A) in vitro and in cells overexpressing G9a or GLP. The chromodomain of MPP8 recognizes the dimethylated Dnmt3aK44me2. MPP8 also interacts with self-methylated GLP in a methylation-dependent manner. The MPP8 chromodomain forms a dimer in solution and in crystals, suggesting that a dimeric MPP8 molecule could bridge the methylated Dnmt3a and GLP, resulting in a silencing complex of Dnmt3a-MPP8-GLP/G9a on chromatin templates. Together, these findings provide a molecular explanation, at least in part, for the co-occurrence of DNA methylation and H3K9 methylation in chromatin.

| S-EPMC3286832 | biostudies-literature

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