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 7

JMJD3 regulates PDLIM4 by facilitating the interaction between KLF2 and WDR5.

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JMJD3 regulates PDLIM4 by facilitating the interaction between KLF2 and ...
(A) 293T cells were cotransfected with HA-Klf2 and FLAG-tagged Ash2L, RbBP5, Wdr5, or Dpy30. WCLs were immunoprecipitated with anti-FLAG beads and immunoblotted with anti-HA Abs. (B) WCLs from WT and Jmjd3-cKO CD4 SP T cells were immunoprecipitated with anti-KLF2 Abs and immunoblotted with anti-JMJD3, WDR5, and KLF2 Abs, respectively. (C) Schematic presentation of cloned HA-tagged N- and C-terminal regions of KLF2. (D) 293T cells were cotransfected with HA–N-terminal, HA–C-terminal, or full-length Klf2 along with FLAG-Wdr5. WCLs were immunoprecipitated with anti-FLAG beads and immunoblotted with anti-HA Abs. (E) 293T cells were cotransfected with HA–N-terminal, HA–C-terminal, or full-length Klf2 along with FLAG-Jmjd3. WCLs were immunoprecipitated with anti-FLAG beads and immunoblotted with anti-HA Abs. (F) 293T cells were cotransfected with HA–N-terminal, HA–C-terminal, or the middle region of Jmjd3 along with HA-Klf2. WCLs were immunoprecipitated with anti-Klf2 Abs and immunoblotted with anti-HA Abs. (G) 293T cells were cotransfected with HA–N-terminal, HA–C-terminal, or the middle region of JMJD3 along with FLAG-Ash2L. WCLs were immunoprecipitated with anti-FLAG Abs and immunoblotted with anti-HA Abs. (H) Schematic diagram of proposed mechanism of how JMJD3 and KLF2 regulate Pdlim4 expression. JMJD3 interacts with the MLL4 protein ASH2L and forms a stable complex with KLF2, which is capable of binding to the Pdlim4 promoter. This permits JMJD3 to alter the H3K27 methylation state of Pdlim4 and permits ASH2L to alter H3K4 methylation to control Pdlim4 expression.