Abstract
Histone H3K9 methyltransferase (HMTase) G9a-mediated transcriptional repression is a major epigenetic silencing mechanism. UHRF1 (ubiquitin-like with PHD and ring finger domains 1) binds to hemimethylated DNA and plays an essential role in the maintenance of DNA methylation. Here, we provide evidence that UHRF1 is transcriptionally downregulated by H3K9 HMTase G9a. We found that increased expression of G9a along with transcription factor YY1 specifically represses UHRF1 transcription during TPA-mediated leukemia cell differentiation. Using ChIP analysis, we found that UHRF1 was among the transcriptionally silenced genes during leukemia cell differentiation. Using a DNA methylation profiling array, we discovered that the UHRF1 promoter was hypomethylated in samples from leukemia patients, further supporting its overexpression and oncogenic activity. Finally, we showed that G9a regulates UHRF1-mediated H3K23 ubiquitination and proper DNA replication maintenance. Therefore, we propose that H3K9 HMTase G9a is a specific epigenetic regulator of UHRF1.
Highlights
The structure of chromatin is dynamically regulated by various posttranslational modifications of the core histones
Among different epigenetic regulators of UHRF1 transcription, we focused on H3K9 methyltransferase (HMTase) related to transcriptional repression
We further describe the extended role of H3K9 HMTase G9a in leukemia cells by showing its negative regulation of UHRF1 transcription
Summary
The structure of chromatin is dynamically regulated by various posttranslational modifications of the core histones. Those modifications influence the folding and functional status of chromatin and thereby eventually control gene expression [1,2]. Lysine methylation regulates diverse substrates, including histones and non-histone proteins, and correlates with distinct biological outcomes, including transcriptional regulation. G9a/GLP methylate non-histone proteins, including p53, CDYL1 and Reptin, and have been shown to automethylate as well [9,10,11,12]. One report suggested that G9a/GLP activity promotes H3K9-me patterning in human hematopoietic stem and progenitor cells (HSPCs) and that its inhibition delays HSPC lineage commitment [13]. Loss of G9a significantly delayed disease progression and reduced leukemia stem cell frequency in an acute myeloid leukemia mouse model [14]
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