Effect of CUL4B on T helper differentiation

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 and plasticity. 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 and plasticity. In vivo, an aggravated Th2 response caused by the absence of CUL4B was observed in a murine asthma model. Mechanistically, the CUL4B complex promoted monoubiquitination at H2AK119 (H2AK119ub1) and trimethylation at H3K27 (H3K27me3) at Tbx21 and Maf and consequently repressed their expression during Th cell differentiation. Our study suggests that CUL4B complex-mediated H2AK119ub1 deposition functions to prevent the aberrant expression of Th1 and Th2 lineage-specific genes.