Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.
Blood. 2013 Aug 29;122(9):1545-55. doi: 10.1182/blood-2013-04-496281. Epub 2013 Jun 18.
Histone methylation is a dynamic and reversible process proposed to directly impact on stem cell fate. The Jumonji (JmjC) domain-containing family of demethylases comprises 27 members that target mono-, di-, and trimethylated lysine residues of histone (or nonhistone) proteins. To evaluate their role in regulation of hematopoietic stem cell (HSC) behavior, we performed an in vivo RNAi-based functional screen and demonstrated that Jarid1b and Jhdm1f play opposing roles in regulation of HSC activity. Decrease in Jarid1b levels correlated with an in vitro expansion of HSCs with preserved long-term in vivo lymphomyeloid differentiation potential. Through RNA sequencing analysis, Jarid1b knockdown was associated with increased expression levels of several HSC regulators (Hoxa7, Hoxa9, Hoxa10, Hes1, Gata2) and reduced levels of differentiation-associated genes. shRNA against Jhdmlf, in contrast, impaired hematopoietic reconstitution of bone marrow cells. Together, our studies identified Jarid1b as a negative regulator of HSC activity and Jhdmlf as a positive regulator of HSC activity.
组蛋白甲基化是一个动态和可逆的过程，被认为直接影响干细胞的命运。含有 JmjC 结构域的去甲基酶家族由 27 个成员组成，它们靶向组蛋白（或非组蛋白）蛋白的单、二和三甲基化赖氨酸残基。为了评估它们在调节造血干细胞（HSC）行为中的作用，我们进行了基于 RNAi 的体内功能筛选，并证明了 Jarid1b 和 Jhdm1f 在调节 HSC 活性方面发挥着相反的作用。Jarid1b 水平的降低与体外扩增具有保留的体内淋巴髓系分化潜能的 HSCs 相关。通过 RNA 测序分析，Jarid1b 敲低与几个 HSC 调节因子（Hoxa7、Hoxa9、Hoxa10、Hes1、Gata2）的表达水平升高和分化相关基因的水平降低相关。相反，针对 Jhdmlf 的 shRNA 会损害骨髓细胞的造血重建。总之，我们的研究确定了 Jarid1b 是 HSC 活性的负调节剂，而 Jhdmlf 是 HSC 活性的正调节剂。
