Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model

Karamitros Timokratis; Hurst Tara; Marchi EmanueleKaramichali EiriniGeorgopoulou UraniaMentis AndreasRiepsaame JoeyLin AudreyParaskevis DimitriosHatzakis AngelosMcLauchlan JohnKatzourakis ArisMagiorkinis Gkikas

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America. >Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model

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Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model

机译：Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model

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HERV-K HML-2 (HK2) has been proliferating in the germ line of humans at least as recently as 250,000 years ago, with some integrations that remain polymorphic in the modern human population. One of the solitary HK2 LTR polymorphic integrations lies between exons 17 and 18 of RASGRF2, a gene that affects dopaminergic activity and is thus related to addiction. Here we show that this antisense HK2 integration (namely RASGRF2-int) is found more frequently in persons who inject drugs compared with the general population. In a Greek HIV-1-positive population (n = 202), we found RASGRF2-int 2.5 times (14 versus 6) more frequently in patients infected through i.v. drug use compared with other transmission route controls (P = 0.03). Independently, in a United Kingdom-based hepatitis C virus-positive population (n = 184), we found RASGRF2-int 3.6 times (34 versus 9.5) more frequently in patients infected during chronic drug abuse compared with controls (P 0.001). We then tested whether RASGRF2-int could be mechanistically responsible for this association by modulating transcription of RASGRF2. We show that the CRISPR/Cas9-mediated insertion of HK2 in HEK293 cells in the exact RASGRF2 intronic position found in the population resulted in significant transcriptional and phenotypic changes. We also explored mechanistic features of other intronic HK2 integrations and show that HK2 LTRs can be responsible for generation of cis-natural antisense transcripts, which could interfere with the transcription of nearby genes. Our findings suggest that RASGRF2-int is a strong candidate for dopaminergic manipulation, and emphasize the importance of accurate mapping of neglected HERV polymorphisms in human genomic studies.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2018年第41期|10434-10439|共6页
作者
Karamitros Timokratis; Hurst Tara; Marchi EmanueleKaramichali EiriniGeorgopoulou UraniaMentis AndreasRiepsaame JoeyLin AudreyParaskevis DimitriosHatzakis AngelosMcLauchlan JohnKatzourakis ArisMagiorkinis Gkikas;
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作者单位

Hellenic Pasteur Inst, Dept Microbiol, Mol Virol Lab, Athens 11527, Greece;

Hellenic Pasteur Inst, Dept Microbiol, Publ Hlth Labs, Athens 11527, Greece;

Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, EnglandUniv Oxford, Dept Zool, Oxford OX1 3PS, EnglandUniv Athens, Med Sch, Dept Hyg Epidemiol & Med Stat, Athens 11527, GreeceUniv Glasgow, Ctr Virus Res, MRC, Glasgow G61 1QH, Lanark, ScotlandUniv Oxford, Nuffield Dept Med, Oxford OX1 3SY, England;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
HERV-K HML-2; endogenous retrovirus; RASGRF2; persons who inject drugs; addiction;

Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model

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