Decreased SUV39H1 at the promoter region leads to increased CREMα and accelerates autoimmune response in CD4+ T cells from patients with systemic lupus erythematosus

Clin Epigenetics. 2022 Dec 20;14(1):181. doi: 10.1186/s13148-022-01411-7.

Abstract

Background: Overproduction of cAMP-responsive element modulator α (CREMα) in total T cells from patients with systemic lupus erythematosus (SLE) can inhibit IL-2 and increase IL-17A. These ultimately promote progression of SLE. This study aims to investigate the expression of CREMα in SLE CD4+ T cells and find out the mechanisms for the regulation of CREMα in SLE CD4+ T cells.

Results: CREMα mRNA was overexpressed in CD4+ T cells from SLE patients. The levels of histone H3 lysine 9 trimethylation (H3K9me3) and suppressor of variation 3-9 homolog 1 (SUV39H1) at the CREMα promoter of SLE CD4+ T cells were markedly decreased. Down-regulating SUV39H1 in normal CD4+ T cells elevated the levels of CREMα, IL-17A, and histone H3 lysine 4 trimethylation (H3K4me3) in the CREMα promoter region, and lowered IL-2, H3K9me3, DNA methylation, and DNA methyltransferase 3a (DNMT3a) enrichments within the CREMα promoter, while no sharp change in SET domain containing 1 (Set1) at the CREMα promoter. Up-regulating SUV39H1 in SLE CD4+ T cells had the opposite effects. The DNA methylation and DNMT3a levels were obviously reduced, and H3K4me3 enrichment was greatly increased at the CREMα promoter of CD4+ T cells from SLE patients. The Set1 binding in the CREMα promoter region upgraded significantly, and knocking down Set1 in SLE CD4+ T cells alleviated the H3K4me3 enrichment within this region, suppressed CREMα and IL-17A productions, and promoted the levels of IL-2, CREMα promoter DNA methylation, and DNMT3a. But there were no obviously alterations in H3K9me3 and SUV39H1 amounts in the region after transfection.

Conclusions: Decreased SUV39H1 in the CREMα promoter region of CD4+ T cells from SLE patients contributes to under-expression of H3K9me3 at this region. In the meantime, the Set1 binding at the CREMα promoter of SLE CD4+ T cells is up-regulated. As a result, DNMT3a and DNA methylation levels alleviate, and H3K4me3 binding increases. All these lead to overproduction of CREMα. Thus, the secretion of IL-2 down-regulates and the concentration of IL-17A up-regulates, ultimately promoting SLE.

Keywords: CREMα; DNA methylation; DNMT3a; H3K4me3; H3K9me3; SUV39H1; Set1; Systemic lupus erythematosus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmunity / genetics
  • CD4-Positive T-Lymphocytes / metabolism
  • Cyclic AMP Response Element Modulator* / metabolism
  • DNA Methylation
  • DNA Methyltransferase 3A
  • Histones* / metabolism
  • Humans
  • Interleukin-17 / genetics
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Lupus Erythematosus, Systemic* / genetics
  • Lysine / metabolism
  • Methyltransferases* / genetics
  • Promoter Regions, Genetic
  • Repressor Proteins* / genetics
  • T-Lymphocytes / metabolism

Substances

  • DNA Methyltransferase 3A
  • Histones
  • Interleukin-17
  • Interleukin-2
  • Lysine
  • Methyltransferases
  • Repressor Proteins
  • SUV39H1 protein, human
  • CREM protein, human
  • Cyclic AMP Response Element Modulator