The histone demethylase Kdm3a is essential to progression through differentiation

Herzog, Mariëlle; Josseaux, Eléonore; Dedeurwaerder, Sarah; Calonne, Emilie; Volkmar, Michael; Fuks, François

doi:10.1093/nar/gks399

Cited by 31 publications

(24 citation statements)

References 40 publications

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“…Knock down of the Kdm3a product, Jmjd1a, was shown to affect a large number of downstream targets; global mRNA expression showed that 125 genes were up‐regulated and 100 genes were down‐regulated [Loh et al, ]. Kdm3a has essential role in early embryonic differentiation with crucial regulatory and inductor function for a number of specific downstream genes [Herzog et al, ]. Complete knockout of Jmjd1a causes adult onset obesity, hyperlipidemia, and other signs of metabolic syndrome [Tateishi et al, ].…”

Section: Resultsmentioning

confidence: 99%

“…Complete knockout of Jmjd1a causes adult onset obesity, hyperlipidemia, and other signs of metabolic syndrome [Tateishi et al, ]. We are unaware of pathogenic KDM3A variants for ID, although there are reports of somatic mutations implicated in cancer [Herzog et al, ]. ClinGen reported a ∼400 kb loss variant (nssv577707) including KDM3A and two adjacent genes in a patient with “developmental delay and additional significant developmental and morphological phenotypes.” A DECIPHER loss CNV, two gains in DECIPHER and two gains in ClinGen completely include this gene; however, all are several Mb in size.…”

Section: Resultsmentioning

confidence: 99%

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Intragenic CNVs for epigenetic regulatory genes in intellectual disability: Survey identifies pathogenic and benign single exon changes

Zahir

Tucker

Mayo

et al. 2016

American J of Med Genetics Pt A

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The disruption of genes involved in epigenetic regulation is well known to cause Intellectual Disability (ID). We reported a custom microarray study that interrogated among others, the epigenetic regulatory gene-class, at single exon resolution. Here we elaborate on identified intragenic CNVs involving epigenetic regulatory genes; specifically discussing those in three genes previously unreported in ID etiology-ARID2, KDM3A, and ARID4B. The changes in ARID2 and KDM3A are likely pathogenic while the ARID4B variant is uncertain. Previously, we found a CNV involving only exon 6 of the JARID2 gene occurred apparently de novo in seven patients. JARID2 is known to cause ID and other neurodevelopmental conditions. However, exon 6 of this gene encodes one of a series of repeated motifs. We therefore, investigated the impact of this variant in two cohorts and present a genotype-phenotype assessment. We find the JARID2 exon 6 CNV is benign, with a high population frequency (>14%), but nevertheless could have a contributory effect. We also present results from an interrogation of the exomes of 2,044 patients with neurocognitive phenotypes for the incidence of potentially damaging mutation in the epigenetic regulatory gene-class. This paper provides a survey of the fine-scale CNV landscape for epigenetic regulatory genes in the context of ID, describing likely pathogenic as well as benign single exon imbalances. © 2016 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Intragenic CNVs for epigenetic regulatory genes in intellectual disability: Survey identifies pathogenic and benign single exon changes

Zahir

Tucker

Mayo

et al. 2016

American J of Med Genetics Pt A

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“…This regulation is unexpected of a direct Jmjd1a/G9a epigenetic function and may instead be due to changes in the H3K9 methylation status or expression of antiangiogenic genes that produce microenvironments conducive or detrimental to the maintenance of stem celllike populations, respectively. The significant effects of Jmjd1a/ G9a with the onset of hypoxia during tumor formation, in contrast to the lack of pluripotency defects in ES cells, highlight the effect of hypoxia on the expression of pluripotency genes and further suggest that Jmjd1a/G9a may become important only upon exit from self-renewal and the subsequent onset of differentiation, rather than at ES cell self-renewal stages (48), affecting the status of stem cell-like populations needed for tumor growth.…”

Section: Discussionmentioning

confidence: 98%

The Hypoxia-Inducible Epigenetic Regulators Jmjd1a and G9a Provide a Mechanistic Link between Angiogenesis and Tumor Growth

Ueda

Lee

et al. 2014

Molecular and Cellular Biology

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dHypoxia promotes stem cell maintenance and tumor progression, but it remains unclear how it regulates long-term adaptation toward these processes. We reveal a striking downregulation of the hypoxia-inducible histone H3 lysine 9 (H3K9) demethylase JMJD1A as a hallmark of clinical human germ cell-derived tumors, such as seminomas, yolk sac tumors, and embryonal carcinomas. Jmjd1a was not essential for stem cell self-renewal but played a crucial role as a tumor suppressor in opposition to the hypoxia-regulated oncogenic H3K9 methyltransferase G9a. Importantly, loss of Jmjd1a resulted in increased tumor growth, whereas loss of G9a produced smaller tumors. Pharmacological inhibition of G9a also resulted in attenuation of tumor growth, offering a novel therapeutic strategy for germ cell-derived tumors. Finally, Jmjd1a and G9a drive mutually opposing expression of the antiangiogenic factor genes Robo4, Igfbp4, Notch4, and Tfpi accompanied by changes in H3K9 methylation status. Thus, we demonstrate a novel mechanistic link whereby hypoxia-regulated epigenetic changes are instrumental for the control of tumor growth through coordinated dysregulation of antiangiogenic gene expression. Growing solid tumors develop shortages of oxygen (hypoxia) and nutrient supplies. Cancer cells induce the formation of new blood vessels from surrounding host tissues to overcome these adverse conditions. Hypoxia-inducible factors (HIFs) drive the transcriptome of cells to adapt to low-oxygen conditions (1-3). It is now increasingly evident that cancer cells adapted to hypoxia have more-malignant phenotypes (4-7). These findings raise the possibility that hypoxia effectuates long-term adaptation to low-oxygen conditions by altering the epigenetic landscape of cancer cells. However, how hypoxia, HIFs, and possibly other coregulated proteins affect the epigenetic status of oxygen-deprived cancer cells to promote malignancy remains largely unknown.To examine the impact of hypoxia on cancers, we previously examined global gene expression profiles of seven human cell lines of diverse cancer origins and found that JMJD1A (Jumonji domain-containing 1A, also known as JHDM2A and KDM3A) is one of the epigenetic factors most commonly induced by hypoxia (3). Consistent with this result, other studies have shown that JMJD1A and other Jumonji domain-containing proteins are upregulated in response to hypoxia and that HIF-1␣ is directly involved in this activation (8, 9). Jumonji domain-containing proteins have been identified as histone lysine demethylases and require Fe(II) and ␣-ketoglutarate for their catalytic activity (10). Among them, JMJD1A demethylates mono-and dimethylated histone H3 lysine 9 (H3K9) residues. JMJD1A also acts as a coactivator in cooperation with the androgen receptor (11), and it has been proposed to operate downstream of HIF-1␣ to activate target genes under hypoxic conditions (9). While Jmjd1a Ϫ/Ϫ mice are viable, males show defects in spermatogenesis leading to infertility, and both genders display an obese phenotype (12)(13)(...

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“…KDM3A also has a role in maintaining pluripotency in ESCs by demethylation of H3K9 leading to expression of pluripotency factors. The same study found that KDM4C also regulates maintenance of pluripotency via H3K9 demethylation [111]. KDM4A and KDM4B are essential to Drosophila development and mediate ecdysteriod hormone signaling leading to transcriptional activation of ecdysone response genes [112].…”

Section: Jmjc-kdms and Developmentmentioning

confidence: 91%

Epigenetic Regulation by Histone Demethylases in Hypoxia

et al. 2015

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The response to hypoxia is primarily mediated by the hypoxia-inducible transcription factor (HIF). Levels of HIF are regulated by the oxygen-sensing HIF hydroxylases, members of the 2-oxoglutarate (2OG) dependent oxygenase family. JmjC-domain containing histone lysine demethylases (JmjC-KDMs), also members of the 2OG oxygenase family, are key epigenetic regulators that modulate the methylation levels of histone tails. Kinetic studies of the JmjC-KDMs indicate they could also act in an oxygen-sensitive manner. This may have important implications for epigenetic regulation in hypoxia. In this review we examine evidence that the levels and activity of JmjC-KDMs are sensitive to oxygen availability, and consider how this may influence their roles in early development and hypoxic disease states including cancer and cardiovascular disease.

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The histone demethylase Kdm3a is essential to progression through differentiation

Cited by 31 publications

References 40 publications

Intragenic CNVs for epigenetic regulatory genes in intellectual disability: Survey identifies pathogenic and benign single exon changes

Intragenic CNVs for epigenetic regulatory genes in intellectual disability: Survey identifies pathogenic and benign single exon changes

The Hypoxia-Inducible Epigenetic Regulators Jmjd1a and G9a Provide a Mechanistic Link between Angiogenesis and Tumor Growth

Epigenetic Regulation by Histone Demethylases in Hypoxia

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