Epigenetic Regulation of Mouse Sex Determination by the Histone Demethylase Jmjd1a

Kuroki, Shunsuke; Matoba, Shogo; Akiyoshi, Mika; Matsumura, Yukiko; Miyachi, Hitoshi; Mise, Nathan; Abe, Kuniya; Ogura, Atsuo; Wilhelm, Dagmar; Koopman, Peter; Nozaki, Masami; Kanai‐Azuma, Masami; Shinkai, Yoichi; Tachibana, Makoto

doi:10.1126/science.1239864

Cited by 222 publications

(200 citation statements)

References 25 publications

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“…Interestingly, a recent study has demonstrated that Jmjd1a-deficient mice display defects in sex determination and abnormal spermiogenesis (47), indicating that Jmjd1a is critical for germ cell development. Given that germ cell tumors are themselves derived from cells of embryonic origin, we therefore decided to study the molecular basis of hypoxia-regulated epigenetics using mouse ES cells as the common denominator for both tumor and stem cell development.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Recently, epigenetic mechanisms have been demonstrated to regulate genes involved in sex determination and gonadal differentiation (Kuroki et al, 2013;Piferrer, 2013;Shao et al, 2014;Tachibana, 2015;Zhang et al, 2013). Epigenetic mechanisms, including DNA methylation, histone modification and non-coding RNAs, can integrate environmental information with the regulation of gene expression, and have been emerging as a promising regulatory mechanism for TSD (Matsumoto et al, 2013a;Navarro-Martín et al, 2011;Parrott et al, 2014;Piferrer, 2013;Venegas et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Dmrt1 induces the male pathway in a turtle with temperature-dependent sex determination

Ye²,

Zhang

et al. 2017

Development

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The molecular mechanism underlying temperature-dependent sex determination (TSD) has been a long-standing mystery; in particular, the thermosensitive genetic triggers for gonadal sex differentiation are largely unknown. Here, we have characterized a conserved DM domain gene, Dmrt1, in the red-eared slider turtle Trachemys scripta (T. scripta), which exhibits TSD. We found that Dmrt1 has a temperature-dependent, sexually dimorphic expression pattern, preceding gonadal sex differentiation, and is capable of responding rapidly to temperature shifts and aromatase inhibitor treatment. Most importantly, loss-and gain-of-function analyses provide solid evidence that Dmrt1 is both necessary and sufficient to initiate male development in T. scripta. Furthermore, the DNA methylation dynamics of the Dmrt1 promoter are tightly correlated with temperature and could mediate the impact of temperature on sex determination. Collectively, our findings demonstrate that Dmrt1 is a candidate master male sex-determining gene in this TSD species, consistent with the idea that DM domain genes are conserved during the evolution of sex determination mechanisms.

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“…They include Kdm3a, a H3K9 histone demethylase which directly regulate the expression of Sry by modifying the chromatin conformation upstream of Sry (Kuroki et al, 2013). Nr0b1, also known as Dax1, encodes a member of the orphan nuclear hormone receptor family.…”

Section: Sertoli Cell Differentiation Program Is Regulated By Waves Omentioning

confidence: 99%

Deciphering cell lineage specification during male sex determination with single-cell RNA sequencing

Stévant

Neirijnck

Borel

et al. 2017

Preprint

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Epigenetic Regulation of Mouse Sex Determination by the Histone Demethylase Jmjd1a

Cited by 222 publications

References 25 publications

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

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

Dmrt1 induces the male pathway in a turtle with temperature-dependent sex determination

Deciphering cell lineage specification during male sex determination with single-cell RNA sequencing

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