CRL4B complex-mediated H2AK119 monoubiquitination restrains Th1 and Th2 cell differentiation
CRL4B complex-mediated H2AK119 monoubiquitination restrains Th1 and Th2 cell differentiation
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DOI：
10.1038/s41418-023-01155-8
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发表时间：
2023-04-06
影响因子：
12.4
通讯作者：
Li，Peishan
中科院分区：
文献类型：
--
作者：
Qin，Liping;Song，Yu;Li，Peishan
CD 4 +T辅助细胞（Th）分化受转录因子的谱系特异性表达调节，这与表观遗传修饰（包括组蛋白乙酰化和甲基化）密切相关。然而，调节Th细胞分化中所涉及的组蛋白修饰的因素在很大程度上仍然未知。我们在此证明了Cullin 4 B（CUL 4 B）在限制Th 1和Th 2细胞分化中的关键作用。CUL 4 B组装成CUL 4 B-RING E3连接酶（CRL 4 B）复合物，通过转录的表观遗传抑制参与各种生理和发育过程。Cul 4 bin CD 4 +T细胞的耗竭增强了Th 1和Th 2细胞的分化。在体内，在小鼠哮喘模型中观察到由CUL 4 B的缺乏引起的Th 2应答加重。在机制上，CRL 4 B复合物促进在Tbx 21和Maf处的H2 AK 119（H2 AK 119 ub 1）处的单泛素化和多梳抑制复合物2（PRC 2）介导的H3 K27（H3 K27 me 3）处的三甲基化，从而抑制它们在Th细胞分化期间的表达。我们的研究表明，CRL 4 B复合物介导的H2 AK 119 ub 1沉积功能，以防止异常表达的Th 1和Th 2谱系特异性基因。
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 ofCul4bin 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) atTbx21andMafand 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.