Self-renewing somatic tissues rely on progenitors to support the continuous tissue regeneration. The gene regulatory network maintaining progenitor function remains incompletely understood. Here we show that NUP98 and RAE1 are highly expressed in epidermal progenitors, forming a separate complex in the nucleoplasm. Reduction of NUP98 or RAE1 abolishes progenitors’ regenerative capacity, inhibiting proliferation and inducing premature terminal differentiation. Mechanistically, NUP98 binds on chromatin near the transcription start sites of key epigenetic regulators (such as DNMT1, UHRF1 and EZH2) and sustains their expression in progenitors. NUP98’s chromatin binding sites are co-occupied by HDAC1. HDAC inhibition diminishes NUP98’s chromatin binding and dysregulates NUP98 and RAE1’s target gene expression. Interestingly, HDAC inhibition further induces NUP98 and RAE1 to localize interdependently to the nucleolus. These findings identified a pathway in progenitor maintenance, where HDAC activity directs the high levels of NUP98 and RAE1 to directly control key epigenetic regulators, escaping from nucleolar aggregation.

自我更新的体细胞组织依靠祖细胞来支持持续的组织再生。维持祖细胞功能的基因调控网络仍不完全清楚。在这里，我们发现 NUP98 和 RAE1 在表皮祖细胞中高度表达，在核质中形成单独的复合物。 NUP98 或 RAE1 的减少会消除祖细胞的再生能力，抑制增殖并诱导过早的终末分化。从机制上讲，NUP98 结合在关键表观遗传调节因子（例如DNMT1 、 UHRF1和EZH2 ）转录起始位点附近的染色质上，并维持它们在祖细胞中的表达。 NUP98 的染色质结合位点与 HDAC1 共同占据。 HDAC 抑制会减少 NUP98 的染色质结合并失调 NUP98 和 RAE1 的靶基因表达。有趣的是，HDAC 抑制进一步诱导 NUP98 和 RAE1 相互依赖地定位于核仁。这些发现确定了祖细胞维持的一条途径，其中 HDAC 活性指导高水平的 NUP98 和 RAE1 直接控制关键的表观遗传调节因子，从而逃避核仁聚集。