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