Aberrant expression pattern of histone acetylation modifiers and mitigation of lupus by SIRT1-siRNA in MRL/lpr mice

Abstract

Objective: Aberrant histone acetylation is implicated in the epigenetic mechanism of lupus. In this study, we investigated the role of the enzymes that catalyse histone acetylation or deacetylation, in particular the histone deacetylase (HDAC) SIRT1, in lupus pathogenesis using a lupus mouse model.

Methods: Samples from 10 MRL/lpr mice and 10 MRL/MPJ wild-type mice, both female and 18 weeks old, were studied to determine the differential expression of three histone acetyltransferases (HATs) and six HDACs. Then, 18 female MRL/lpr mice, all 18 weeks old, received tail vein injections of SIRT1-siRNA or control treatments, and were killed 24 h, 5 days, or 10 days later. Urine protein and serum anti-nuclear antibody (ANA) and anti-dsDNA antibody levels were measured. SIRT1 expression and histone acetylation levels were determined in splenic CD4+ T cells. Renal pathology and renal immunoglobulin (Ig)G deposition were scored.

Results: The transcription of P300, PCAF, and HDAC7 decreased, while SIRT1 expression increased in CD4+ T cells of MRL/lpr mice, compared to MRL/MPJ mice. After administration of SIRT1-siRNA into the MRL/lpr mice, SIRT1 expression was suppressed and global histone H3 and H4 acetylation levels were elevated transiently in CD4+ T cells. Moreover, serum anti-dsDNA antibody level, renal IgG deposition, and renal pathological scores, particularly tubulointerstitial scores, decreased significantly. Urine protein and serum ANA levels did not change significantly.

Conclusion: An aberrant expression pattern of HATs and HDACs exists in CD4+ T cells of MRL/lpr mice, among which SIRT1 overexpression is implicated in lupus pathogenesis and SIRT1-siRNA mitigates the damage of lupus in vivo in MRL/lpr mice.