Structural insights into a novel histone demethylase PHF8

Lin, Yongjun; Wang, Yan; Huang, Shuo; Wang, Jianjun; Deng, Zhichao; Zhang, Qi; Wu, Wei; Zhang, Xingliang; Liu, Zhao; Gong, Weimin; Chen, Zhongzhou

doi:10.1038/cr.2010.8

Cited by 70 publications

(49 citation statements)

References 36 publications

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“…PHF8 was shown to be a histone demethylase for H3K9me2, H3K27me2, and H3K36me2 [23]. However, three reports identified PHF8 as a histone demethylase specific for H3K9me2 [21,24,25], which are consistent with our results. According to the proposed nomenclature for chromatin-modifying enzymes [26], PHF8 should be named as lysine demethylase 7B (KDM7B), since its close homolog KIAA1718 was named as KDM7A [22].…”

Section: Discussionsupporting

confidence: 82%

PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis

Zhu

Wang

et al. 2010

Cell Res

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Dimethylation of histone H3 lysine 9 (H3K9me2) is an important epigenetic mark associated with transcription repression. Here, we identified PHF8, a JmjC-domain-containing protein, as a histone demethylase specific for this repressing mark. Recombinant full-length wild type protein could remove methylation from H3K9me2, but mutation of a conserved histidine to alanine H247A abolished the demethylase activity. Overexpressed exogenous PHF8 was colocalized with B23 staining. Endogenous PHF8 was also colocalized with B23 and fibrillarin, two well-established nucleolus proteins, suggesting that PHF8 is localized in the nucleolus and may regulate rRNA transcription. Indeed, PHF8 bound to the promoter region of the rDNA gene. Knockdown of PHF8 reduced the expression of rRNA, and overexpression of the gene resulted in upregulation of rRNA transcript. Concomitantly, H3K9me2 level was elevated in the promoter region of the rDNA gene in PHF8 knockdown cells and reduced significantly when the wild type but not the catalytically inactive H247A mutant PHF8 was overexpressed. Thus, our study identified a histone demethylase for H3K9me2 that regulates rRNA transcription.

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Section: Discussionsupporting

confidence: 82%

PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis

Zhu

Wang

et al. 2010

Cell Res

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“…Based on in vitro demethylation assays Loenarz et al first reported that PHF8 catalyzed demethylation of H3K9me2/1, H3K27me2 and H3K36me2 [28]. Other studies show PHF8 as a predominant H3K9me2/1 demethylase with either minimal H3K27me2 and H3K36me2 demethylase activity [29] or H3K9me2/1 demethylase activity only [30][31][32][33]. In agreement with the latter studies, we showed that in all assays PHF8 exhibited histone demethylase activity with H3K9me2/1 specificity.…”

Section: Discussionsupporting

confidence: 68%

The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation

et al. 2010

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Recent studies have identified mutations in PHF8, an X-linked gene encoding a JmjC domain-containing protein, as a causal factor for X-linked mental retardation (XLMR) and cleft lip/cleft palate. However, the underlying mechanism is unknown. Here we show that PHF8 is a histone demethylase and coactivator for retinoic acid receptor (RAR). Although activities for both H3K4me3/2/1 and H3K9me2/1 demethylation were detected in cellularbased assays, recombinant PHF8 exhibited only H3K9me2/1 demethylase activity in vitro, suggesting that PHF8 is an H3K9me2/1 demethylase whose specificity may be modulated in vivo. Importantly, a mutant PHF8 (phenylalanine at position 279 to serine) identified in the XLMR patients is defective in enzymatic activity, indicating that the loss of histone demethylase activity is causally linked with the onset of disease. In addition, we show that PHF8 binds specifically to H3K4me3/2 peptides via an N-terminal PHD finger domain. Consistent with a role for PHF8 in neuronal differentiation, knockdown of PHF8 in mouse embryonic carcinoma P19 cells impairs RA-induced neuronal differentiation, whereas overexpression of the wild-type but not the F279S mutant PHF8 drives P19 cells toward neuronal differentiation. Furthermore, we show that PHF8 interacts with RARα and functions as a coactivator for RARα. Taken together, our results suggest that histone methylation modulated by PHF8 plays a critical role in neuronal differentiation.

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“…Recently, Yu et al demonstrated the catalytic specificity of human PHF8 by determining its crystal structure [7]. Working with wild type (WT) PHF8 and a PHD deletion mutant (c-PHF8) discussed below, they showed that human c-PHF8 consists of 16 α helices and 12 β-strands, arranged in a similar manner to a known JmjC-domain-containing histone demethylase (JHDM1a) [7].…”

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confidence: 99%

“…Working with wild type (WT) PHF8 and a PHD deletion mutant (c-PHF8) discussed below, they showed that human c-PHF8 consists of 16 α helices and 12 β-strands, arranged in a similar manner to a known JmjC-domain-containing histone demethylase (JHDM1a) [7]. In the presence of Fe 2+ and αKG, Fe 2+ sits in the center of the c-PHF8 catalytic core, which consists of nine hydrophobic residues.…”

mentioning

confidence: 99%