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G9a orchestrates PCL3 and KDM7A to promote histone H3K27 methylation.


ABSTRACT: Methylation of histone H3-lysine 9 (H3K9) and H3K27 by the methyltransferase G9a and polycomb repressive complex 2 (PRC2) inhibits transcription of target genes. A crosstalk between G9a and PRC2 via direct physical interaction has been shown recently. Here, we demonstrate an alternative mechanism by which G9a promotes H3K27 methylation. Overexpression of G9a increases both H3K9 and H3K27 methylation, reduces E-cadherin expression, and induces epithelial-mesenchymal transition in PANC-1 pancreatic cancer cells. Conversely, the depletion of G9a or ectopic expression of methyltransferase-dead G9a in G9a-overexpressing gemcitabine-resistant PANC-1-R cells exhibits opposite effects. G9a promotes H3K27 methylation of the E-cadherin promoter by upregulating PCL3 to increase PRC2 promoter recruitment and by downregulating the H3K27 demethylase KDM7A to silence E-cadherin gene. The depletion of PCL3 or overexpression of KDM7A elevated expression of E-cadherin in PANC-1-R cells while ectopic expression of PCL3 or knockdown of KDM7A downregulated E-cadherin in PANC-1 cells. Collectively, we provide evidence that G9a orchestrates the dynamic balance within histone-modifying enzymes to regulate H3K27 methylation and gene expression.

SUBMITTER: Pan MR 

PROVIDER: S-EPMC4685317 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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G9a orchestrates PCL3 and KDM7A to promote histone H3K27 methylation.

Pan Mei-Ren MR   Hsu Ming-Chuan MC   Chen Li-Tzong LT   Hung Wen-Chun WC  

Scientific reports 20151221


Methylation of histone H3-lysine 9 (H3K9) and H3K27 by the methyltransferase G9a and polycomb repressive complex 2 (PRC2) inhibits transcription of target genes. A crosstalk between G9a and PRC2 via direct physical interaction has been shown recently. Here, we demonstrate an alternative mechanism by which G9a promotes H3K27 methylation. Overexpression of G9a increases both H3K9 and H3K27 methylation, reduces E-cadherin expression, and induces epithelial-mesenchymal transition in PANC-1 pancreati  ...[more]

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