Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Stem Cells. 2023 Oct 8;41(10):971-985. doi: 10.1093/stmcls/sxad058.
Recent studies suggest that chromosomal cohesin complex proteins are important in regulating hematopoiesis and may contribute to myeloid malignancies. To investigate the effects of perturbing the cohesin subunit protein RAD21 on normal hematopoiesis, we used conditional knockout (cKO) mouse models. While cohesin is vital for hematopoietic stem cell (HSC) function, Rad21 haploinsufficiency (Rad21Δ/+) led to distinct hematopoietic phenotypes. Our findings revealed that Rad21Δ/+ cells exhibited decreased hematopoietic reconstitution in competitive bone marrow transplantation assays. This reduction in peripheral blood chimerism was specifically observed in the lymphoid compartment, while the chimerism in the myeloid compartment remained unaffected. Rad21 haploinsufficiency also resulted in changes in the hematopoietic stem and progenitor cells (HSPC) and myeloid progenitor compartments, with a significant accumulation of granulocyte-macrophage progenitors in the bone marrow. We observed differential gene expression in Rad21Δ/+ LSK (Lin- Sca1-Kit+) cells, including genes required for HSPC function and differentiation, such as Setdb1, Hmga2, Ncor1, and Myb. In addition, we observed a notable decrease in the expression of genes related to the interferon response and a significant reduction in the expression of genes involved in the IL2-STAT5 signaling pathways. Our studies suggest that RAD21 protein and level of its post-translational modifications in the bone marrow cells may play a potential role in hematopoiesis. Overall, Rad21 haploinsufficiency impairs hematopoietic differentiation and increases HSC self-renewal.
最近的研究表明，染色质黏合复合物蛋白在调节造血过程中起着重要作用，并且可能与髓系恶性肿瘤有关。为了研究干扰黏合亚基蛋白 RAD21 对正常造血的影响，我们使用了条件性敲除（cKO）小鼠模型。尽管黏合对于造血干细胞（HSC）功能至关重要，但 RAD21 杂合不足（Rad21Δ/+）导致了明显的造血表型。我们的研究结果表明，Rad21Δ/+ 细胞在竞争性骨髓移植实验中表现出造血重建能力下降。在外周血嵌合率中，这种减少主要发生在淋巴系，而骨髓中的嵌合率不受影响。Rad21 杂合不足还导致造血干/祖细胞（HSPC）和髓系祖细胞区室发生变化，骨髓中粒细胞-巨噬细胞祖细胞显著积累。我们观察到 Rad21Δ/+ LSK（Lin-Sca1-Kit+）细胞中的差异基因表达，包括 HSPC 功能和分化所需的基因，如 Setdb1、Hmga2、Ncor1 和 Myb。此外，我们观察到与干扰素反应相关的基因表达显著降低，并且与 IL2-STAT5 信号通路相关的基因表达显著减少。我们的研究表明，RAD21 蛋白及其在骨髓细胞中的翻译后修饰水平可能在造血过程中发挥潜在作用。总的来说，Rad21 杂合不足会损害造血分化并增加 HSC 自我更新。
