Polycomb group (PcG) proteins play important roles in hematopoietic stem cell (HSC) self-renewal. Mel18 and Bmi1 are homologs of the PCGF subunit within the Polycomb repressive complex 1 (PRC1). Bmi1 (PCGF4) enhances HSC self-renewal and promotes terminal differentiation. However, the role of Mel18 (PCGF2) in hematopoiesis is not fully understood and how Mel18 regulates gene transcription in HSCs remains elusive. We found that acute deletion of Mel18 in the hematopoietic compartment significantly increased the frequency of functional HSCs in the bone marrow. Furthermore, we demonstrate that Mel18 inhibits HSC self-renewal and proliferation. RNA-seq studies revealed that HSC self-renewal and proliferation gene signatures are enriched in Mel18^−/− hematopoietic stem and progenitors (HSPCs) compared to Mel18^+/+ HSPCs. Notably, ATAC-seq revealed increased chromatin accessibility at genes important for HSC self-renewal, whereas CUT&RUN showed decreased enrichment of H2AK119ub1 at genes important for proliferation, leading to increased expression of both Hoxb4 and Cdk4 in Mel18^−/− HSPCs. Thus, we demonstrate that Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of genes important for HSC self-renewal and proliferation.

多梳组 （PcG） 蛋白在造血干细胞 （HSC） 自我更新中起重要作用。Mel18 和 Bmi1 是多梳抑制复合物 1 （PRC1） 中 PCGF 亚基的同源物。Bmi1 （PCGF4） 增强 HSC 自我更新并促进终末分化。然而，Mel18 （PCGF2） 在造血中的作用尚不完全清楚，Mel18 如何调节 HSC 中的基因转录仍然难以捉摸。我们发现造血区室中 Mel18 的急性缺失显着增加了骨髓中功能性 HSC 的频率。此外，我们证明 Mel18 抑制 HSC 的自我更新和增殖。RNA-seq 研究表明，与 Mel18^+/+ HSPC 相比，HSC 自我更新和增殖基因特征在 Mel18 ^{- /-} 造血干细胞和祖细胞 （HSPC） 中富集。值得注意的是，ATAC-seq 显示对 HSC 自我更新重要的基因的染色质可及性增加，而 CUT&RUN 显示 H2AK119ub1 在对增殖重要的基因上的富集降低，导致 Hoxb4 的表达增加和 Cdk4 在 Mel18 ^{− / −} HSPCs 中。因此，我们证明 Mel18 通过抑制对 HSC 自我更新和增殖很重要的基因的转录来抑制造血干细胞的自我更新。