Transcriptomic Profiling and H3K27me3 Distribution Reveal Both Demethylase-Dependent and Independent Regulation of Developmental Gene Transcription in Cell Differentiation

Kang, Sung Chul; Kim, Se Kye; Chai, Jin Choul; Kim, Sun Hwa; Won, Kyoung Jae; Lee, Young Seek; Jung, Kyoung Hwa; Chai, Young Gyu

doi:10.1371/journal.pone.0135276

Cited by 16 publications

(14 citation statements)

References 63 publications

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“…In support of this notion, we did not find increased H3K27 methylation in the promoter region of putative KDM6 target genes in KDM6A-KO KDM6-KD cells, despite a global increase in H3K27me3 levels. These results further support previous findings indicating a demethylaseindependent function of KDM6 for the regulation of developmental gene expression (Kang et al, 2015;Lee et al, 2012). In contrast to what might be expected upon global upregulation of a repressive chromatin mark, the majority of differentially expressed genes were expressed at higher levels following GSK-J4 treatment.…”

Section: Discussionsupporting

confidence: 90%

Inhibition of KDM6 activity during murine ESC differentiation induces DNA damage

Hofstetter¹,

Kampka²,

Huppertz³

et al. 2016

Development

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Pluripotent embryonic stem cells (ESCs) are characterised by their capacity to self-renew indefinitely while maintaining the potential to differentiate into all cell types of an adult organism. Both the undifferentiated and differentiated states are defined by specific gene expression programs that are regulated at the chromatin level. Here, we have analysed the contribution of the H3K27me2-and H3K27me23-specific demethylases KDM6A and KDM6B to murine ESC differentiation by employing the GSK-J4 inhibitor, which is specific for KDM6 proteins, and by targeted gene knockout (KO) and knockdown. We observe that inhibition of the H3K27 demethylase activity induces DNA damage along with activation of the DNA damage response (DDR) and cell death in differentiating but not in undifferentiated ESCs. Laser microirradiation experiments revealed that the H3K27me3 mark, but not the KDM6B protein, colocalise with γH2AX-positive sites of DNA damage in differentiating ESCs. Lack of H3K27me3 attenuates the GSK-J4-induced DDR in differentiating Eed-KO ESCs. Collectively, our findings indicate that differentiating ESCs depend on KDM6 and that the H3K27me3 demethylase activity is crucially involved in DDR and survival of differentiating ESCs.

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Section: Discussionsupporting

confidence: 90%

Inhibition of KDM6 activity during murine ESC differentiation induces DNA damage

Hofstetter¹,

Kampka²,

Huppertz³

et al. 2016

Development

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“…The function of histone methylation is mainly reflected in heterochromatin forming, genomic imprinting, X chromosome inactivation and transcriptional control (46)(47)(48)(49)(50)(51)(52). Apart from histone methyltransferase, the histone demethylase is also found (53,54). At first, it was considered that the histone methylation effect was stable and irreversible; however, the existence of methyltransferase renders the process of histone methylation more dynamical.…”

Section: Histone Methylationmentioning

confidence: 99%

Histone lysine methylation and congenital heart disease: From bench to bedside (Review)

Jiang

et al. 2017

International Journal of Molecular Medicine

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Histone post-translational modifications (PTM) as one of the key epigenetic regulatory mechanisms that plays critical role in various biological processes, including regulating chromatin structure dynamics and gene expression. Histone lysine methyltransferase contributes to the establishment and maintenance of differential histone methylation status, which can recognize histone methylated sites and build an association between these modifications and their downstream processes. Recently, it was found that abnormalities in the histone lysine methylation level or pattern may lead to the occurrence of many types of cardiovascular diseases, such as congenital heart disease (CHD). In order to provide new theoretical basis and targets for the treatment of CHD from the view of developmental biology and genetics, this review discusses and elaborates on the association between histone lysine methylation modifications and CHD.

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“…Hoxa11 is a Jmjd3 target in differentiating bone marrow cells (26). During differentiation of a human embryonic carcinoma cell line, HoxB1 upregulation was shown to be repressed by Jmjd3 − / − mutants (29). Conversely, during macrophage differentiation, the levels of H3K27me3 at Hoxa7 and Hoxa9 were not different between Jmjd3 − / − and wild‐type cells (30).…”

mentioning

confidence: 99%

New insights into the role of Jmjd3 and Utx in axial skeletal formation in mice

et al. 2017

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Jmjd3 and Utx are demethylases specific for lysine 27 of histone H3. Previous reports indicate that Jmjd3 is essential for differentiation of various cell types, such as macrophages and epidermal cells in mice, whereas Utx is involved in cancer and developmental diseases in humans and mice, as well as regulation in zebrafish and nematodes. Here, we report that Jmjd3, but not Utx, is involved in axial skeletal formation in mice. A Jmjd3 mutant embryo (), but not a catalytically inactive Utx truncation mutant (), showed anterior homeotic transformation. Quantitative RT-PCR and microarray analyses showed reduced expression in both embryos and tailbuds, whereas levels of activators, such as Wnt signaling factors and retinoic acid synthases, did not decrease, which suggests that Jmjd3 plays a regulatory role in expression during axial patterning. Chromatin immunoprecipitation analyses of embryo tailbud tissue showed trimethylated lysine 27 on histone H3 to be at higher levels at the loci in mutants compared with wild-type tailbuds. In contrast, trimethylated lysine 4 on histone H3 levels were found to be equivalent in wild-type and tailbuds. Demethylase-inactive Jmjd3 mutant embryos showed the same phenotype as mice. These results suggest that the demethylase activity of Jmjd3, but not that of Utx, affects mouse axial patterning in concert with alterations in gene expression.-Naruse, C., Shibata, S., Tamura, M., Kawaguchi, T., Abe, K., Sugihara, K., Kato, T., Nishiuchi, T., Wakana, S., Ikawa, M., Asano, M. New insights into the role of Jmjd3 and Utx in axial skeletal formation in mice.

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Transcriptomic Profiling and H3K27me3 Distribution Reveal Both Demethylase-Dependent and Independent Regulation of Developmental Gene Transcription in Cell Differentiation

Cited by 16 publications

References 63 publications

Inhibition of KDM6 activity during murine ESC differentiation induces DNA damage

Inhibition of KDM6 activity during murine ESC differentiation induces DNA damage

Histone lysine methylation and congenital heart disease: From bench to bedside (Review)

New insights into the role of Jmjd3 and Utx in axial skeletal formation in mice

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