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.
Hughes and Sawalha Arthritis Research & Therapy 2011 13:245 doi:10.1186/ar3484