Cell fate is determined by specific transcription programs that are essential for tissue homeostasis and regeneration. The E3-ligases RING1A and B represent the core activity of the Polycomb repressive complex 1 (PRC1) that deposits repressive histone H2AK119 mono-ubiquitination (H2AK119ub1), which is essential for mouse intestinal homeostasis by preserving stem cell functions. However, the specific role of different PRC1 forms, which are defined by the six distinct PCGF1–6 paralogs, remains largely unexplored in vivo.

We report that PCGF6 regulates mouse intestinal Tuft cell differentiation independently of H2AK119ub1 deposition. We show that PCGF6 chromatin occupancy expands outside Polycomb repressive domains, associating with unique promoter and distal regulatory elements. This occurs in the absence of RING1A/B and involves MGA-mediated E-BOX recognition and specific H3K9me2 promoter deposition. PCGF6 inactivation induces an epithelial autonomous accumulation of Tuft cells that was not phenocopied by RING1A/B loss. This involves direct PCGF6 association with a Tuft cell differentiation program that identified Polycomb-independent properties of PCGF6 in adult tissues homeostasis.

细胞命运由特定的转录程序决定，这对于组织稳态和再生至关重要。 E3 连接酶 RING1A 和 B 代表 Polycomb 抑制复合物 1 (PRC1) 的核心活性，该复合物沉积抑制性组蛋白 H2AK119 单泛素化 (H2AK119ub1)，这对于通过保护干细胞功能来维持小鼠肠道稳态至关重要。然而，不同 PRC1 形式（由六种不同的 PCGF1-6 旁系同源物定义）的具体作用在体内仍然很大程度上未被探索。

我们报告 PCGF6 独立于 H2AK119ub1 沉积调节小鼠肠道簇细胞分化。我们发现 PCGF6 染色质占据扩展到 Polycomb 抑制域之外，与独特的启动子和远端调控元件相关。这种情况发生在 RING1A/B 不存在的情况下，涉及 MGA 介导的 E-BOX 识别和特定的 H3K9me2 启动子沉积。 PCGF6 失活会诱导簇细胞的上皮自主积累，但 RING1A/B 缺失并未体现出这种现象。这涉及 PCGF6 与簇细胞分化程序的直接关联，该程序确定了 PCGF6 在成体组织稳态中不依赖于多梳的特性。