JMJD3 regulates CD4+ T cell trafficking by targeting actin cytoskeleton regulatory gene Pdlim4
Chuntang Fu, … , Helen Y. Wang, Rong-Fu Wang
Chuntang Fu, … , Helen Y. Wang, Rong-Fu Wang
Published August 8, 2019
Citation Information: J Clin Invest. 2019;129(11):4745-4757. https://doi.org/10.1172/JCI128293.
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Research Article Autoimmunity Cell biology Immunology

JMJD3 regulates CD4+ T cell trafficking by targeting actin cytoskeleton regulatory gene Pdlim4

Abstract

Histone H3K27 demethylase JMJD3 plays a critical role in gene expression and T cell differentiation. However, the role and mechanisms of JMJD3 in T cell trafficking remain poorly understood. Here, we show that JMJD3 deficiency in CD4+ T cells resulted in an accumulation of T cells in the thymus and reduction of T cell number in the secondary lymphoid organs. We identified PDLIM4 as a significantly downregulated target gene in JMJD3-deficient CD4+ T cells by gene profiling and ChIP-Seq analyses. We further showed that PDLIM4 functioned as an adaptor protein to interact with sphingosine-1 phosphate receptor 1 (S1P1) and filamentous actin (F-actin), thus serving as a key regulator of T cell trafficking. Mechanistically, JMJD3 bound to the promoter and gene-body regions of the Pdlim4 gene and regulated its expression by interacting with zinc finger transcription factor KLF2. Our findings have identified Pdlim4 as a JMJD3 target gene that affects T cell trafficking by cooperating with S1P1 and have provided insights into the molecular mechanisms by which JMJD3 regulates genes involved in T cell trafficking.

Authors

Chuntang Fu, Qingtian Li, Jia Zou, Changsheng Xing, Mei Luo, Bingnan Yin, Junjun Chu, Jiaming Yu, Xin Liu, Helen Y. Wang, Rong-Fu Wang

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Figure 6

H3K27me3 and H3K4me3 levels in the Pdlim4 promoter in WT and Jmjd3-deficient T cells.

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H3K27me3 and H3K4me3 levels in the Pdlim4 promoter in WT and Jmjd3-defic...
(A) ChIP-Seq analysis of H3K27me3 and H3K4me3 levels in the promoter and gene-body regions of Klf2, S1p1, and Pdlim4 in thymic CD4 SP T cells isolated from WT and Jmjd3-cKO mice. Red boxes indicate 2 kb regions around the TSS. Scale bars: 5 kb. (B) Validation of methylation changes on the Pdlim4 gene in WT and Jmjd3-cKO CD4 SP T cells by ChIP-qPCR. Data represent mean ± SD from 3 independent experiments. n = 3. *P < 0.05, Student’s t test. (C) Luciferase assay was performed on 293T cells cotransfected with Pdlim4 promoter–linked episomal luciferase vector and with Klf2 in the presence of WT or mutant Jmjd3 (a loss of demethylase function mutation). Data are presented as mean ± SD from 3 independent experiments. n = 3. **P < 0.01, 1-way ANOVA with Tukey’s multiple comparisons test.