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CRL4B complex-mediated H2AK119 monoubiquitination restrains Th1 and Th2 cell differentiation

Cell Death & Differentiation volume 30, pages 1488–1502 (2023)Cite this article

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Abstract

CD4+ T helper (Th) cell differentiation is regulated by lineage-specific expression of transcription factors, which is tightly associated with epigenetic modifications, including histone acetylation and methylation. However, the factors regulating histone modifications involved in Th cell differentiation remain largely unknown. We herein demonstrated a critical role of Cullin 4B (CUL4B) in restricting Th1 and Th2 cell differentiation. CUL4B, which is assembled into the CUL4B-RING E3 ligase (CRL4B) complex, participates in various physiological and developmental processes through epigenetic repression of transcription. Depletion of Cul4b in CD4+ T cells enhanced Th1 and Th2 cell differentiation. In vivo, an aggravated Th2 response caused by the absence of CUL4B was observed in a murine asthma model. Mechanistically, the CRL4B complex promoted monoubiquitination at H2AK119 (H2AK119ub1) and polycomb repressive complex 2 (PRC2)-mediated trimethylation at H3K27 (H3K27me3) at Tbx21 and Maf and consequently repressed their expression during Th cell differentiation. Our study suggests that CRL4B complex-mediated H2AK119ub1 deposition functions to prevent the aberrant expression of Th1 and Th2 lineage-specific genes.

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Fig. 1: Depletion of CUL4B in T cells upregulates the expression of Th1 and Th2 cell differentiation-associated genes.
Fig. 2: Loss of CUL4B enhances Th1 and Th2 differentiation in vitro.
Fig. 3: Loss of CUL4B enhances plasticity between Th1 and Th2 cells in vitro.
Fig. 4: CUL4B deficiency enhances the Th2 cell-mediated immune response in murine models.
Fig. 5: CRL4B restrains Th1 and Th2 cell differentiation by repressing T-bet and c-Maf expression.
Fig. 6: CRL4B-dependent H2AK119ub1 and EZH2-dependent H3K27me3 modifications are associated with silencing of lineage-specific loci during Th cell differentiation.
Fig. 7: Depletion of CUL4B reduces H2AK119ub1 and H3K27me3 levels at lineage-specific loci.

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Data availability

Raw and processed data for RNA-seq can be obtained from PRJNA929073 in NCBI Sequence Read Archive (SRA) database. All of the full-length original western blots for these results are provided. All other datasets are available upon request from the corresponding authors.

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Acknowledgements

We thank Translational Medicine Core Facility of Shandong University for technical support.

Funding

This study was supported by grants from the National Natural Science Foundation of China (31872810) to YG, (31970559) to BJ, Suzhou Science and Technology Bureau (ZXL2021440) to PL, the Natural Science Foundation of Jiangsu Province (BK20211543) to PL, and the Natural Science Foundation of Shandong Province (ZR2016HZ01) to YG.

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Authors and Affiliations

  1. Key Laboratory of Experimental Teratology, Ministry of Education, Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Liping Qin, Yu Song, Fan Zhang, Ru Wang, Li Zhou, Shiqi Jin, Molin Wang, Baichun Jiang, Yaoqin Gong & Peishan Li

  2. Key Laboratory of Experimental Teratology, Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Chaojia Chen & Chunhong Ma

  3. Key Laboratory of Experimental Teratology, Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Chunyang Li & Gongping Sun

  4. State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Suzhou Medical College, Soochow University, Suzhou, 215123, Jiangsu, China

    Peishan Li

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  1. Liping Qin
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Contributions

PL, YG, and LQ designed the study. LQ, YS, RW, CC, LZ, and SJ performed experiments. FZ analyzed the RNA-seq data. PL, YG, and LQ interpreted the data and wrote the paper. CL, CM, GS, MW, BJ reviewed and edited the paper. YG and PL supervised the project.

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Correspondence to Yaoqin Gong or Peishan Li.

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Qin, L., Song, Y., Zhang, F. et al. CRL4B complex-mediated H2AK119 monoubiquitination restrains Th1 and Th2 cell differentiation. Cell Death Differ 30, 1488–1502 (2023). https://doi.org/10.1038/s41418-023-01155-8

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