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 3

An increased accessibility of the Il21 promoter is observed in CKO CD4+ T cells, and severity of Blimp-1 deficiency–mediated colitis can be restored by histone acetyltransferase CBP/p300 inhibitor.

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An increased accessibility of the Il21 promoter is observed in CKO CD4+ ...
(A–H) Genome-wide ATAC-Seq data tracks for chromatin accessibility were detected for indicated T cells from 12-week-old mice. (A) Numbers of open chromatin regions were identified in each genotype. (B) DARs were identified in CD4+ T cells from indicated mice. (C) The distributions of DARs in either promoters or gene bodies from indicated cells. (D) Heatmap displaying DARs (peak site) in promoters (I) and gene bodies (II) in CKO CD4+ T cells and DARs in promoters (III) and gene bodies (IV) in control T cells. (E) Venn diagram illustrating the intersection of upregulated DEGs identified by RNA-Seq and the genes with DARs in promoters detected by ATAC-Seq in Blimp-1 CKO CD4+ T cells. (F) Visualization of the overlapping genes in E. (G) Representative sequencing tracks for the Il21, Cxcr5, and Pdcd1 loci showing ATAC-Seq signals. (H) The peak abundance of Il21, Cxcr5, and Pdcd1 in indicated cells. (I) IPA of significantly represented diseases for IL-21–dependent inflammatory disorders in CKO T cells. (J–O) CKO mice were treated with CBP30 twice a week from 12 to 25 weeks old. Incidence of diarrhea (J), total body weights (K), and survival curves (L) at various ages (n = 7 mice/group). (M) Representative colon sections and histological score from indicated mice at age 25 weeks. (N and O) Percentages of IL-21+CD4+ T cells (N) as well as Il21 RNA expression (O) in indicated mice. Data represent the mean ± SEM of at least 3 independent experiments; *P < 0.05; **P < 0.01; ***P < 0.001; significance was determined using unpaired Student’s 2-tailed t test (H, M, and O), 1-way ANOVA (N), or log-rank test (J–L).