@article{186456,
  keywords = {Humans, Transcription Factors, HeLa Cells, Female, Aged, Middle Aged, DNA Methylation, Epigenesis, Genetic, Adult, Young Adult, Adolescent, Terminal Repeat Sequences, Adaptor Proteins, Signal Transducing, Alleles, TOR Serine-Threonine Kinases, T-Lymphocytes, Receptors, Antigen, T-Cell, HCT116 Cells, DNA (Cytosine-5-)-Methyltransferase 1, Endogenous Retroviruses, Lupus Erythematosus, Systemic, Nuclear Respiratory Factor 1},
  author = {Aparna* Godavarthy and Ryan* Kelly and John Jimah and Miguel Beckford and Tiffany Caza and David Fernandez and Nick Huang and Manuel Duarte and Joshua Lewis and Hind Fadel and Eric Poeschla and Katalin Banki and Andras Perl},
  title = {Lupus-associated endogenous retroviral LTR polymorphism and epigenetic imprinting promote HRES-1/RAB4 expression and mTOR activation},
  abstract = {<p>Overexpression and long terminal repeat (LTR) polymorphism of the HRES-1/Rab4 human endogenous retrovirus locus have been associated with T cell activation and disease manifestations in systemic lupus erythematosus (SLE). Although genomic DNA methylation is diminished overall in SLE, its role in HRES-1/Rab4 expression is unknown. Therefore, we determined how lupus-associated polymorphic rs451401 alleles of the LTR regulate transcription from the HRES-1/Rab4 promoter and thus affect T cell activation. The results showed that cytosine-119 is hypermethylated while cytosine-51 of the promoter and the LTR enhancer are hypomethylated in SLE. Pharmacologic or genetic inactivation of DNA methyltransferase 1 augmented the expression of HRES-1/Rab4. The minimal promoter was selectively recognized by metabolic stress sensor NRF1 when cytosine-119 but not cytosine-51 was methylated, and NRF1 stimulated HRES-1/Rab4 expression in human T cells. In turn, IRF2 and PSIP1 bound to the LTR enhancer and exerted control over HRES-1/Rab4 expression in rs451401 genotype- and methylation-dependent manners. The LTR enhancer conferred markedly greater expression of HRES-1/Rab4 in subjects with rs451401CC over rs451401GG alleles that in turn promoted mechanistic target of rapamycin (mTOR) activation upon T cell receptor stimulation. HRES-1/Rab4 alone robustly activated mTOR in human T cells. These findings identify HRES-1/Rab4 as a methylation- and rs451401 allele-dependent transducer of environmental stress and controller of T cell activation.</p>
},
  year = {2020},
  journal = {JCI Insight},
  volume = {5},
  month = {01/2020},
  issn = {2379-3708},
  doi = {10.1172/jci.insight.134010},
  language = {eng},
}