Blimp-1 molds the epigenetic architecture of IL-21–mediated autoimmune diseases through an autoregulatory circuit
Yu-Wen Liu, Shin-Huei Fu, Ming-Wei Chien, Chao-Yuan Hsu, Ming-Hong Lin, Jia-Ling Dong, Rita Jui-Hsien Lu, Yi-Jing Lee, Pao-Yang Chen, Chih-Hung Wang, Huey-Kang Sytwu
Yu-Wen Liu, Shin-Huei Fu, Ming-Wei Chien, Chao-Yuan Hsu, Ming-Hong Lin, Jia-Ling Dong, Rita Jui-Hsien Lu, Yi-Jing Lee, Pao-Yang Chen, Chih-Hung Wang, Huey-Kang Sytwu
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Research Article Cell biology

Blimp-1 molds the epigenetic architecture of IL-21–mediated autoimmune diseases through an autoregulatory circuit

Abstract

Positive regulatory domain 1 (PRDM1) encodes B lymphocyte–induced maturation protein 1 (BLIMP1), also known as a master regulator of T cell homeostasis. We observed a negative relationship between Blimp-1 and IL-21 based on our previous data that Blimp-1 overexpression in T cells suppresses autoimmune diabetes while Blimp-1–deficient T cells contribute to colitis in NOD mice. Reanalysis of published data sets also revealed an inverse correlation between PRDM1 and IL21 in Crohn’s disease. Here, we illustrate that Blimp-1 repressed IL-21 by reducing chromatin accessibility and evicting an IL-21 activator, c-Maf, from the Il21 promoter. Moreover, Blimp-1 overexpression–mediated reduction in permissive chromatin structures at the Il21 promoter could override IL-21–accelerated autoimmune diabetogenesis in small ubiquitin-like modifier–defective c-Maf–transgenic mice. An autoregulatory feedback loop to harness IL-21 expression was unveiled by the evidence that IL-21 addition induced time-dependent Blimp-1 expression and subsequently enriched its binding to the Il21 promoter to suppress IL-21 overproduction. Furthermore, intervention of this feedback loop by IL-21 blockade, with IL-21R.Fc administration or IL-21 receptor deletion, attenuated Blimp-1 deficiency–mediated colitis and reinforced the circuit between Blimp-1 and IL-21 in the regulation of autoimmunity. We highlight the translation of Blimp-1–based epigenetic and transcriptomic profiles applicable to a personalized medicine approach in autoimmune diseases.

Authors

Yu-Wen Liu, Shin-Huei Fu, Ming-Wei Chien, Chao-Yuan Hsu, Ming-Hong Lin, Jia-Ling Dong, Rita Jui-Hsien Lu, Yi-Jing Lee, Pao-Yang Chen, Chih-Hung Wang, Huey-Kang Sytwu

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Figure 2

The Blimp-1 consensus binding site is essential for suppressing Il21 promoter activity through the formation of repressive chromatin structures.

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The Blimp-1 consensus binding site is essential for suppressing Il21 pro...
(A) EL4 cells were cotransfected with an Il21 promoter–driven luciferase reporter and various concentrations of Blimp-1–expressing vector as indicated. (B) CD4+CD25– T cells were cultured under anti-CD3/anti-CD28 stimulation alone (Th0) or Th1- or Th17-polarized conditions. After 3 days, a luciferase assay was performed by cotransfecting the luciferase reporter and empty vectors (pcDNA3.1) or Blimp-1–expressing vectors. (C) Wild-type Blimp-1– or truncated Blimp-1–expressing vector (ΔDBD) was cotransfected with Il21 promoter into EL4 cells. Then luciferase activity was determined. (D) Luciferase assays were performed by cotransfecting Blimp-1–expressing vectors and vectors containing an Il21 promoter that either was full-length or contained a 5 bp (GAAAG) deletion or a site-directed mutation. (E) CD4+ T cells were isolated from indicated mice and stimulated with anti-CD3/anti-CD28 antibodies for 6 days, then restimulated with PMA and ionomycin for 4 hours, to evaluate enrichment of Blimp-1 on the Il21 promoter with (site 1) or without (site 2) Blimp-1 binding sites and the Snail3 locus (site 3). (F) CD4+ T cells were stimulated for 5 days and ChIP assays were performed using indicated antibodies. Data represent the mean ± SEM of at least 3 independent experiments; *P < 0.05; **P < 0.01; ***P < 0.001. Significance was determined by 1-way ANOVA (A–F).