PMID- 31805010
OWN - NLM
STAT- MEDLINE
DCOM- 20210510
LR  - 20240403
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 5
IP  - 1
DP  - 2020 Jan 16
TI  - Lupus-associated endogenous retroviral LTR polymorphism and epigenetic imprinting 
      promote HRES-1/RAB4 expression and mTOR activation.
LID - 134010 [pii]
LID - 10.1172/jci.insight.134010 [doi]
LID - e134010
AB  - 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.
FAU - Godavarthy, Aparna
AU  - Godavarthy A
AD  - Division of Rheumatology, Department of Medicine.
FAU - Kelly, Ryan
AU  - Kelly R
AD  - Division of Rheumatology, Department of Medicine.
FAU - Jimah, John
AU  - Jimah J
AD  - Division of Rheumatology, Department of Medicine.
FAU - Beckford, Miguel
AU  - Beckford M
AD  - Division of Rheumatology, Department of Medicine.
FAU - Caza, Tiffany
AU  - Caza T
AD  - Division of Rheumatology, Department of Medicine.
AD  - Department of Microbiology and Immunology, and.
FAU - Fernandez, David
AU  - Fernandez D
AD  - Division of Rheumatology, Department of Medicine.
AD  - Department of Microbiology and Immunology, and.
FAU - Huang, Nick
AU  - Huang N
AD  - Division of Rheumatology, Department of Medicine.
AD  - Department of Biochemistry and Molecular Biology, State University of New York, 
      Upstate Medical University, College of Medicine, Syracuse, New York, USA.
FAU - Duarte, Manuel
AU  - Duarte M
AD  - Division of Rheumatology, Department of Medicine.
FAU - Lewis, Joshua
AU  - Lewis J
AD  - Division of Rheumatology, Department of Medicine.
FAU - Fadel, Hind J
AU  - Fadel HJ
AD  - Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, New 
      York, USA.
FAU - Poeschla, Eric M
AU  - Poeschla EM
AD  - Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, New 
      York, USA.
FAU - Banki, Katalin
AU  - Banki K
AD  - Department of Pathology, State University of New York, Upstate Medical 
      University, College of Medicine, Syracuse, New York, USA.
FAU - Perl, Andras
AU  - Perl A
AD  - Division of Rheumatology, Department of Medicine.
AD  - Department of Microbiology and Immunology, and.
AD  - Department of Biochemistry and Molecular Biology, State University of New York, 
      Upstate Medical University, College of Medicine, Syracuse, New York, USA.
LA  - eng
GR  - R56 AI048079/AI/NIAID NIH HHS/United States
GR  - R01 AI122176/AI/NIAID NIH HHS/United States
GR  - U01 AR076092/AR/NIAMS NIH HHS/United States
GR  - R01 AI048079/AI/NIAID NIH HHS/United States
GR  - R01 AI072648/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200116
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (NRF1 protein, human)
RN  - 0 (Nuclear Respiratory Factor 1)
RN  - 0 (PSIP1 protein, human)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Transcription Factors)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase 1)
RN  - EC 2.1.1.37 (DNMT1 protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Alleles
MH  - DNA (Cytosine-5-)-Methyltransferase 1
MH  - DNA Methylation
MH  - Endogenous Retroviruses/*genetics
MH  - *Epigenesis, Genetic
MH  - Female
MH  - HCT116 Cells
MH  - HeLa Cells
MH  - Humans
MH  - Lupus Erythematosus, Systemic/*genetics
MH  - Middle Aged
MH  - Nuclear Respiratory Factor 1
MH  - Receptors, Antigen, T-Cell
MH  - T-Lymphocytes
MH  - TOR Serine-Threonine Kinases/*genetics
MH  - Terminal Repeat Sequences/*genetics/physiology
MH  - Transcription Factors
MH  - Young Adult
PMC - PMC7030820
OTO - NOTNLM
OT  - Immunology
OT  - Lupus
OT  - Rheumatology
OT  - T cells
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2019/12/06 06:00
MHDA- 2021/05/11 06:00
PMCR- 2020/01/16
CRDT- 2019/12/06 06:00
PHST- 2019/10/03 00:00 [received]
PHST- 2019/11/26 00:00 [accepted]
PHST- 2019/12/06 06:00 [pubmed]
PHST- 2021/05/11 06:00 [medline]
PHST- 2019/12/06 06:00 [entrez]
PHST- 2020/01/16 00:00 [pmc-release]
AID - 134010 [pii]
AID - 10.1172/jci.insight.134010 [doi]
PST - epublish
SO  - JCI Insight. 2020 Jan 16;5(1):e134010. doi: 10.1172/jci.insight.134010.