IEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Via Adamello 16, 20139 Milan, Italy.
RIKEN Centre for Integrative Medical Sciences, Laboratory for Developmental Genetics, 1-7-22 Suehiuro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
Dev Cell. 2024 Feb 5;59(3):368-383.e7. doi: 10.1016/j.devcel.2023.12.015. Epub 2024 Jan 15.
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，这些程序对于组织稳态和再生至关重要。E3 连接酶 RING1A 和 B 代表多梳抑制复合物 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），这对于维持干细胞功能的小鼠肠道稳态至关重要。然而，不同 PRC1 形式的特定作用，这些形式由六个不同的 PCGF1-6 同源物定义，在体内仍在很大程度上未被探索。我们报告说，PCGF6 独立于 H2AK119ub1 沉积调节小鼠肠道 Tuft 细胞分化。我们表明，PCGF6 染色质占据会在 Polycomb 抑制结构域外扩展，与独特的启动子和远端调控元件相关。这种情况发生在没有 RING1A/B 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 的失活诱导 Tuft 细胞的上皮自主积累，这不能被 RING1A/B 的缺失所模拟。这涉及直接的 PCGF6 与 Tuft 细胞分化程序的关联，该程序确定了 PCGF6 在成年组织稳态中的多梳非依赖性特性。
