Figure 1.

Epigenetics of lupus CD4+ T cells. A broad DNA methylation defect is observed in lupus CD4+ T cells. Reduced expression of DNA methyltransferase 1 (DNMT1) is observed to lead to the hypomethylation and overexpression of several genes in lupus CD4+ T cells. Specifically, hypomethylation of promoter regions of CD70, CD11a, PRF1, CD40LG (CD40 ligand), and killer immunoglobulin-like receptor (KIR) genes leads to their overexpression and subsequent induction of T-cell autoreactivity. Further, overexpression of GADD45A (growth arrest and DNA-damage-inducible 45 alpha) contributes to decreased DNA methylation in lupus CD4+ T cells. There is overlap between the DNA methylation defect in lupus and other epigenetic mechanisms. Overexpression of miR-148a and miR-126 affect DNA methylation levels by directly targeting DNMT1 transcripts. miR-21 overexpression also affects DNA methylation; however, this microRNA indirectly regulates DNMT1 expression through ERK pathway signaling. Variable expression of other individual regulatory microRNAs also contributes to the disease process. Overexpression of miR-17-92 in murine T lymphocytes is observed and may affect lymphocyte stability. miRNA-155 is overexpressed in CD4+ T cells and contributes to reduced stability of regulatory T cell populations. miR-31 negatively regulates the expression of Foxp3 and has been observed to be overexpressed in murine splenocytes. Underexpression of miR-146 leads to increased type I IFN signaling in lupus CD4+ T cells. Reduced expression of miR-125a leads to increased expression of the inflammatory chemokine RANTES by reduced targeting of KLF13 transcripts. Overexpression of miR-101 has been reported in murine T lymphocytes. miR-101 has also been reported to negatively regulate EZH2, a histone methyltransferase involved in epigenetic repression. Aberrant patterns of histone modification are also observed in lupus CD4+ T cells. Reduced levels of histone 3 lysine 9 trimethylation (H3K9me3) are observed as well as reduced p300 histone acetyltransferase activity. Further, EZH2 levels are reduced in lupus CD4+ T cells. Reduced levels of the transcription factor RFX1 lead to loss of local epigenetic repression characterized by reduced levels of DNA methylation and H3K9me3 via the histone methyltransferase SUV39H1.