Abstract 2409: Loss of L1TD1 suppresses Notch1 induced LINE1 methylation and genomic stability

Autor: Yu-Wei Leu, Wei-Chen Huang, Mei-Ling Kang, Chih-Cheng Chen, Chia-Chen Hsu, Shu-Huei Hsiao, Chia-Chen Chiu, Kuan-Der Lee
Rok vydání: 2017
Předmět:
Zdroj: Cancer Research. 77:2409-2409
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2017-2409
Popis: The silencing of endogenous retrotransposon like LINE1 is critical for the maintenance of genomic stability and the LINE-1 type transposase domain containing 1 (L1TD1) gene possesses the repeated, putative LINE-1 RNA-binding domains and was hypothesized to regulate the activity of LINE-1 through DNA methylation. To verify if L1TD1 is responsible for LINE-1 silencing and the maintenance of somatic genome stability, CRSPR/Cas9 system was used to knockout (KO) L1TD1 locus in gastric, colon and breast cancer cells so as in the mesenchymal stem cells (MSCs). We observed that L1TD1 KO blocked the entrance of SUV39H1, histone methyl transferase, into cell nuclear which suppressed the tri-methylation of histone 3 at lysine 9 (H3k9me3) and LINE-1 methylation. A global demethylation and reduced HP1α recruitment were also observed. The global distribution of CTCF binding loci was also distorted as well as the bivalent histone marks. Further, L1TD1 KO distorted normal distribution of RassF1A expression, cytoskeleton conformation and therefore cell stiffness. The MSC-to-neuron differentiation was also blocked by the KO. Further, we found that overexpressed Notch-1 increased DNA methylation within LINE1 promoter, and this increase was attenuated by L1TD1 KO. Therefore, we conclude that the external signals like Notch1 affect L1NE1 methylation and genome stability through possible LINE1 interacting L1TD1. Since L1TD1 hypermethylation was observed in colon (n=100), gastric (n=19) and breast (n=79) cancers, L1TD1 abnormality is then a candidate for cancer biomarker. (Supported by: MOST-105-2320-B-194-004, MOST-105-2314-B-182A-134, MOST Taiwan and CMRPG6F0092, Chang Gung Memorial Hospital, Chia-Yi, Taiwan) Citation Format: Chia-Chen Chiu, Wei-Chen Huang, Kuan-Der Lee, Chih-Cheng Chen, Chia-Chen Hsu, Mei-Ling Kang, Yu-Wei Leu, Shu-Huei Hsiao. Loss of L1TD1 suppresses Notch1 induced LINE1 methylation and genomic 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 2409. doi:10.1158/1538-7445.AM2017-2409
Databáze: OpenAIRE
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