Abstract
Abstract Piwi-like RNA-mediated gene silencing 4 (PIWIL4) is expressed in somatic tissues and is proposed to silence the transposition of repetitive elements like long interspersed nuclear elements (LINEs) through DNA methylation and maintain the genome stability. Through the knockout of PIWIL4 gene by CRISPR/Cas9 system in mesenchymal stem cells (MSCs), MDA-MB-231 (breast cancer cell line), HT29 (colon cancer cell line) and AGS (gastric cancer cell line), the piRNA biogenesis was decreased and so was the methylation within LINE1 target loci and global methylation. The recruitment of SUV39H1, a histone H3 methyl-transferase, into nucleus was blocked, leading to the reduction of silencing tri-methylation of histone H3 at lysine 9. Concurrently, the active H3K4me3 mark increased after knockout. Also, global CTCF bindings were distorted after the knockout of PIWIL4 especially at the bindings franking the piRNA clusters. This distortion implied the disorganization of genomic conformation which was validated by karyotyping. Through chromosomal G-banding, aneuploidy was observed which indicated the loss of genomic stability. The knockout of PIWIL4 also results in disorganized cytoskeleton, therefore, changed cell stiffness as measured by atomic force microscopy. Neural and hepatic induction of MSCs were also blocked by the knockout of PIWIL4. In correlation, tissue arrays detected abnormal PIWIL4 expression in gastric (n=45), colon (n=30) and breast cancers (n=30). In conclusion, we found that PIWIL4-piRNA interaction helps to maintain somatic DNA methylome, genome stability and stiffness in somatic stem cells. The loss of PIWIL4 expression might then a candidate for cancer biomarker. (Supported by: MOST-105-2314-B-371 -008, MOST-105-2320-B-194 -004, MOST Taiwan) Citation Format: Syuan-Cih Lin, Chia-Chen Chiu, Shou-Tung Chen, Yao-Li Chen, Ping-Yi Lin, Shu-Huei Hsiao, Yu-Wei Leu. Loss of PIWIL4 and piRNAs attenuate somatic methylome and genome stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1398. doi:10.1158/1538-7445.AM2017-1398
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