Bmi1 counteracts hematopoietic stem cell aging by repressing target genes and enforcing the stem cell gene signature.
Bmi1 counteracts hematopoietic stem cell aging by repressing target genes and enforcing the stem cell gene signature.
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DOI：
10.1016/j.bbrc.2019.10.153
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发表时间：
2020-01
影响因子：
3.1
通讯作者：
E. Nitta;Naoki Itokawa;Shogo Yabata;S. Koide;Li-Bo Hou;M. Oshima;Kazumasa Aoyama;A. Saraya;A. Iwama
中科院分区：
文献类型：
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作者：
E. Nitta;Naoki Itokawa;Shogo Yabata;S. Koide;Li-Bo Hou;M. Oshima;Kazumasa Aoyama;A. Saraya;A. Iwama
多梳组蛋白是干细胞的关键调节因子。我们以前证明，Bmi1，polycomb抑制复合物1的一个组成部分，定义了造血干细胞（HSC）的再生能力。在此，我们试图通过调节Bmi 1的表达来改善年龄相关的HSC功能下降。Bmi1的强制表达并没有减弱老年HSC的髓样偏向性分化。然而，单细胞移植实验显示，Bmi 1的持续表达增强了老化HSC的多谱系再生能力。Bmi1染色质免疫沉淀测序结合RNA序列分析表明，大多数Bmi1的直接靶基因是发育调控基因标记的二价组蛋白结构域。Bmi1的持续表达严格维持了其靶基因的转录抑制，并加强了衰老HSC中HSC标签基因的表达。因此，调控Bmi1的表达是一种潜在的抗衰老HSC功能损伤的方法。
Polycomb-group proteins are critical regulators of stem cells. We previously demonstrated that Bmi1, a component of polycomb repressive complex 1, defines the regenerative capacity of hematopoietic stem cells (HSCs). Here, we attempted to ameliorate the age-related decline in HSC function by modulatingBmi1expression. The forced expression ofBmi1did not attenuate myeloid-biased differentiation of aged HSCs. However, single cell transplantation assays revealed that the sustained expression ofBmi1augmented the multi-lineage repopulating capacity of aged HSCs. Chromatin immunoprecipitation-sequencing of Bmi1 combined with an RNA sequence analysis showed that the majority of Bmi1 direct target genes are developmental regulator genes marked with a bivalent histone domain. The sustained expression ofBmi1strictly maintained the transcriptional repression of their target genes and enforced expression of HSC signature genes in aged HSCs. Therefore, the manipulation ofBmi1expression is a potential approach against impairments in HSC function with aging.