RYBP coordinates with Trithorax complex and selectively recruits Polycomb complex for cell fate control

The selective expression is pivotal in orchestrating human development, with the Trithorax Group (TrxG) and Polycomb Group (PcG) complexes playing crucial roles in transcriptional activation and repression, respectively. However, mechanism underlying selective regulation of transcription by TrxG and PcG remains poorly understood. In this study, RYBP was observed to interact with TrxG and PcG components. RYBP and TrxG co-localized loci selectively enriches RING1B. STAT3 enriches at RYBP-TrxG co-localized loci devoid of RING1B, while displaying minimal enrichment at RING1B-enrichred loci. Introduction of STAT3 at RYBP loci disrupted RING1B aggregation and chromatin binding. RYBP-deficiency impairs TrxG deposition at DNA repair genes in RYBP-TrxG loci, consequently diminishing their expression and inducing DNA damage. These results facilitate the transition of embryonic stem cells to 2-cell-like cells. Additionally, RYBP-deficiency attenuates PcG deposition at lineage-specific genes within RYBP-TrxG-RING1B loci, thereby promoting ESC differentiation. Collectively, these results provide novel insights into the selective regulation of gene expression.