PMID- 38153351
OWN - NLM
STAT- MEDLINE
DCOM- 20231229
LR  - 20240106
IS  - 2573-7732 (Electronic)
IS  - 2573-7732 (Linking)
VI  - 7
IP  - 12
DP  - 2023 Dec 1
TI  - Egr2 Deletion in Autoimmune-Prone C57BL6/lpr Mice Suppresses the Expression of 
      Methylation-Sensitive Dlk1-Dio3 Cluster MicroRNAs.
PG  - 898-907
LID - 10.4049/immunohorizons.2300111 [doi]
AB  - We previously demonstrated that the upregulation of microRNAs (miRNAs) at the 
      genomic imprinted Dlk1-Dio3 locus in murine lupus is correlated with global DNA 
      hypomethylation. We now report that the Dlk1-Dio3 genomic region in CD4+ T cells 
      of MRL/lpr mice is hypomethylated, linking it to increased Dlk1-Dio3 miRNA 
      expression. We evaluated the gene expression of methylating enzymes, DNA 
      methyltransferases (DNMTs), and demethylating ten-eleven translocation proteins 
      (TETs) to elucidate the molecular basis of DNA hypomethylation in lupus CD4+ T 
      cells. There was a significantly elevated expression of Dnmt1 and Dnmt3b, as well 
      as Tet1 and Tet2, in CD4+ T cells of three different lupus-prone mouse strains 
      compared to controls. These findings suggest that the hypomethylation of murine 
      lupus CD4+ T cells is likely attributed to a TET-mediated active demethylation 
      pathway. Moreover, we found that deletion of early growth response 2 (Egr2), a 
      transcription factor gene in B6/lpr mice markedly reduced maternally expressed 
      miRNA genes but not paternally expressed protein-coding genes at the Dlk1-Dio3 
      locus in CD4+ T cells. EGR2 has been shown to induce DNA demethylation by 
      recruiting TETs. Surprisingly, we found that deleting Egr2 in B6/lpr mice induced 
      more hypomethylated differentially methylated regions at either the whole-genome 
      level or the Dlk1-Dio3 locus in CD4+ T cells. Although the role of methylation in 
      EGR2-mediated regulation of Dlk1-Dio3 miRNAs is not readily apparent, these are 
      the first data to show that in lupus, Egr2 regulates Dlk1-Dio3 miRNAs, which 
      target major signaling pathways in autoimmunity. These data provide a new 
      perspective on the role of upregulated EGR2 in lupus pathogenesis.
CI  - Copyright (c) 2023 The Authors.
FAU - Wang, Zhuang
AU  - Wang Z
AUID- ORCID: 0000-0001-7822-829X
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Tech, Blacksburg, VA.
FAU - Heid, Bettina
AU  - Heid B
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Tech, Blacksburg, VA.
FAU - He, Jianlin
AU  - He J
AD  - Epigenomics and Computational Biology Lab, Fralin Life Sciences Institute at 
      Virginia Tech, Blacksburg, VA.
FAU - Xie, Hehuang
AU  - Xie H
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Tech, Blacksburg, VA.
AD  - Epigenomics and Computational Biology Lab, Fralin Life Sciences Institute at 
      Virginia Tech, Blacksburg, VA.
FAU - Reilly, Christopher M
AU  - Reilly CM
AUID- ORCID: 0000-0003-4787-7750
AD  - Department of Cell Biology and Physiology, Edward Via College of Osteopathic 
      Medicine, Blacksburg, VA.
FAU - Dai, Rujuan
AU  - Dai R
AUID- ORCID: 0000-0002-1074-8974
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Tech, Blacksburg, VA.
FAU - Ahmed, S Ansar
AU  - Ahmed SA
AUID- ORCID: 0000-0001-5913-7501
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Tech, Blacksburg, VA.
LA  - eng
GR  - 180472/VMCVM Internal Research Competition (IRC) program/
PT  - Journal Article
PL  - United States
TA  - Immunohorizons
JT  - ImmunoHorizons
JID - 101708159
RN  - 0 (MicroRNAs)
RN  - 9007-49-2 (DNA)
RN  - 0 (Dlk1 protein, mouse)
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Egr2 protein, mouse)
RN  - 0 (Early Growth Response Protein 2)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Mice, Inbred MRL lpr
MH  - *DNA Methylation
MH  - Autoimmunity
MH  - Mice, Inbred C57BL
MH  - *MicroRNAs/genetics
MH  - DNA
MH  - Calcium-Binding Proteins/genetics
MH  - Early Growth Response Protein 2
PMC - PMC10759154
COIS- The authors have no financial conflicts of interest.
EDAT- 2023/12/28 12:42
MHDA- 2023/12/29 06:42
PMCR- 2023/12/28
CRDT- 2023/12/28 10:03
PHST- 2023/12/05 00:00 [received]
PHST- 2023/12/06 00:00 [accepted]
PHST- 2023/12/29 06:42 [medline]
PHST- 2023/12/28 12:42 [pubmed]
PHST- 2023/12/28 10:03 [entrez]
PHST- 2023/12/28 00:00 [pmc-release]
AID - 266574 [pii]
AID - immunohorizons_2300111 [pii]
AID - 10.4049/immunohorizons.2300111 [doi]
PST - ppublish
SO  - Immunohorizons. 2023 Dec 1;7(12):898-907. doi: 10.4049/immunohorizons.2300111.