KDM5 Interacts with Foxo to Modulate Cellular Levels of Oxidative Stress

Liu, Xingyin; Greer, Christina; Secombe, Julie

doi:10.1371/journal.pgen.1004676

Cited by 53 publications

(77 citation statements)

References 93 publications

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“…KDM5 A512P affects the ability of KDM5 to activate and repress transcription, since 16% of upregulated and 24% of downregulated genes are direct targets (Figure 2B; Table S1). As previously seen in Drosophila and mammalian systems, changes to gene expression of direct and indirect targets were mild (Iwase et al, 2016; Liu et al, 2014; Liu and Secombe, 2015; Lopez-Bigas et al, 2008; Lussi et al, 2016) (Figure 2C). Because KDM5 A512P affects histone demethylase activity, we also carried out RNA-seq of kdm5 JmjC* adult heads to determine the extent to which loss of enzymatic activity contributed to the transcriptional defects of kdm5 A512P animals.…”

Section: Resultssupporting

confidence: 80%

“…One means by which KDM5 proteins find their target genes is through interactions with sequence-specific transcription factors, including E2F, Myc, Foxo, and the Su(H) complex that acts downstream of Notch signaling (Liefke et al, 2010; Liu et al, 2014; Secombe et al, 2007; van Oevelen et al, 2008). Once at a promoter, KDM5 can affect transcription by demethylating promoter H3K4me3, which is a hallmark of transcriptionally active genes (Johansson et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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A Drosophila Model of Intellectual Disability Caused by Mutations in the Histone Demethylase KDM5

et al. 2018

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SUMMARY Mutations in KDM5 family histone demethylases cause intellectual disability in humans. However, the molecular mechanisms linking KDM5-regulated transcription and cognition remain unknown. Here, we establish Drosophila as a model to understand this connection by generating a fly strain harboring an allele analogous to a disease-causing missense mutation in human KDM5C (kdm5A512P). Transcriptome analysis of kdm5A512P flies revealed a striking downregulation of genes required for ribosomal assembly and function and a concomitant reduction in translation. kdm5A512P flies also showed impaired learning and/or memory. Significantly, the behavioral and transcriptional changes in kdm5A512P flies were similar to those specifically lacking demethylase activity. These data suggest that the primary defect of the KDM5A512P mutation is a loss of histone demethylase activity and reveal an unexpected role for this enzymatic function in gene activation. Because translation is critical for neuronal function, we propose that this defect contributes to the cognitive defects of kdm5A512P flies.

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Section: Resultssupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

A Drosophila Model of Intellectual Disability Caused by Mutations in the Histone Demethylase KDM5

et al. 2018

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“…We therefore, examined the levels of transcripts encoding lysine-specific histone demethylase (KDMs) proteins. Specific members of the KDM family have been implicated in the regulation of the cellular response to oxidative stress (Liu et al, 2014). Almost all the candidate genes examined were reduced in the high oxygen treatment group (Fig.…”

Section: Resultsmentioning

confidence: 99%

Oxygen-induced alterations in the expression of chromatin modifying enzymes and the transcriptional regulation of imprinted genes

Skiles

Kester

Pryor

et al. 2018

Gene Expression Patterns

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Embryo culture and assisted reproductive technologies have been associated with a disproportionately high number of epigenetic abnormalities in the resulting offspring. However, the mechanisms by which these techniques influence the epigenome remain poorly defined. In this study, we evaluated the capacity of oxygen concentration to influence the transcriptional control of a selection of key enzymes regulating chromatin structure. In mouse embryonic stem cells, oxygen concentrations modulated the transcriptional regulation of the TET family of enzymes, as well as the de novo methyltransferase Dnmt3a. These transcriptional changes were associated with alterations in the control of multiple imprinted genes, including H19, Igf2, Igf2r, and Peg3. Similarly, exposure of in vitro produced bovine embryos to atmospheric oxygen concentrations was associated with disruptions in the transcriptional regulation of TET1, TET3, and DNMT3a, along with the DNA methyltransferase co-factor HELLS. In addition, exposure to high oxygen was associated with alterations in the abundance of transcripts encoding members of the Polycomb repressor complex (EED and EZH2), the histone methyltransferase SETDB1 and multiple histone demethylases (KDM1A, KDM4B, and KDM4C). These disruptions were accompanied by a reduction in embryo viability and suppression of the pluripotency genes NANOG and SOX2. These experiments demonstrate that oxygen has the capacity to modulate the transcriptional control of chromatin modifying genes involved in the establishment and maintenance of both pluripotency and genomic imprinting.

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“…In the absence of KDM5, HDAC4 can still form a complex with FOXO1 and induce its deacetylation; however, FOXO1 recruitment to a subset of target genes, which have a role in oxidative stress resistance, is attenuated. This decreased ability of FOXO1 induces the decreased transcriptional activation of a subset of oxidative stress resistance genes (95).…”

Section: Acetylation Of Foxo Proteinsmentioning

confidence: 99%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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Abstract. The Forkhead box O (FOXO) protein family is predominantly involved in apoptosis, oxidative stress, DNA damage/repair, tumor angiogenesis, glycometabolism, regulating life span and other important biological processes. Its activity is affected by a variety of posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, methylation and glycosylation. When cells are subjected to different environments, the corresponding PTMs act on the FOXO protein family, to change transcriptional activity or subcellular localization, and the expression of downstream target genes, will ultimately affect the biological behavior of the cells. In this review, we will discuss the biological characteristics of FOXO protein PTMs.

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KDM5 Interacts with Foxo to Modulate Cellular Levels of Oxidative Stress

Cited by 53 publications

References 93 publications

A Drosophila Model of Intellectual Disability Caused by Mutations in the Histone Demethylase KDM5

A Drosophila Model of Intellectual Disability Caused by Mutations in the Histone Demethylase KDM5

Oxygen-induced alterations in the expression of chromatin modifying enzymes and the transcriptional regulation of imprinted genes

Post-translational modifications of FOXO family proteins

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