Aging alters the epigenetic asymmetry of HSC division.
Aging alters the epigenetic asymmetry of HSC division.
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DOI：
10.1371/journal.pbio.2003389
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发表时间：
2018-09
期刊：
影响因子：
9.8
通讯作者：
Geiger H
中科院分区：
文献类型：
--
作者：
Florian MC;Klose M;Sacma M;Jablanovic J;Knudson L;Nattamai KJ;Marka G;Vollmer A;Soller K;Sakk V;Cabezas-Wallscheid N;Zheng Y;Mulaw MA;Glauche I;Geiger H
造血干细胞（hsc）平衡自我更新和分化以维持体内平衡。随着年龄的增长，极性hsc的出现频率逐渐降低。造血干细胞的细胞极性由小RhoGTPase细胞分裂控制蛋白42 （Cdc42）的活性控制。在这里，我们使用一套全面的配对子细胞分析，包括单细胞3D共聚焦成像、单细胞移植、单细胞RNA-seq和单细胞转座酶可及染色质测序（ATAC-seq），证明了HSC分裂的结果与有丝分裂前的极性状态密切相关，而极性状态反过来又由干细胞中Cdc42的活性水平决定。衰老的极性造血干细胞会优先进行自我更新的对称分裂，导致再生能力和淋巴细胞潜能降低的子干细胞，而年轻的极性造血干细胞则会优先进行不对称分裂。数学模型结合实验数据表明，Cdc42的不对称分选通过表观遗传机制决定子细胞的潜能。因此，控制HSC极性的分子可能作为干细胞分裂模式的调节剂，调节子细胞的潜能。干细胞是一种独特的细胞，可以分化产生更多的干细胞或其他类型的细胞，可以对称分裂（产生具有相同命运的子细胞）和不对称分裂（产生一个保留干细胞潜能的子细胞和一个分化的子细胞）。控制干细胞分裂结果的机制一直是许多研究的焦点；然而，它们主要是未知的。在这里，我们分析了这些机制在小鼠造血干细胞（HSC）中，通过直接比较两个子细胞的表观遗传特征、转录组和功能，这些子细胞来自年轻或年老的HSC的第一次分裂。我们观察到，年轻的造血干细胞主要是不对称分裂，而年老的造血干细胞主要是对称分裂。我们发现分裂模式与干细胞极性密切相关，并受小RhoGTPase细胞分裂控制蛋白42 （Cdc42）的活性水平调节。此外，我们发现子细胞的潜力与表观遗传标记H4K16ac的数量以及分配给子细胞的开放染色质的数量进一步相关，但与其子细胞的转录组无关。总之，我们的研究表明，与Cdc42活性相关的HSC极性驱动分裂模式，而表观遗传机制决定干细胞分裂的功能结果。
Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain homeostasis. With aging, the frequency of polar HSCs decreases. Cell polarity in HSCs is controlled by the activity of the small RhoGTPase cell division control protein 42 (Cdc42). Here we demonstrate—using a comprehensive set of paired daughter cell analyses that include single-cell 3D confocal imaging, single-cell transplants, single-cell RNA-seq, and single-cell transposase-accessible chromatin sequencing (ATAC-seq)—that the outcome of HSC divisions is strongly linked to the polarity status before mitosis, which is in turn determined by the level of the activity Cdc42 in stem cells. Aged apolar HSCs undergo preferentially self-renewing symmetric divisions, resulting in daughter stem cells with reduced regenerative capacity and lymphoid potential, while young polar HSCs undergo preferentially asymmetric divisions. Mathematical modeling in combination with experimental data implies a mechanistic role of the asymmetric sorting of Cdc42 in determining the potential of daughter cells via epigenetic mechanisms. Therefore, molecules that control HSC polarity might serve as modulators of the mode of stem cell division regulating the potential of daughter cells. Stem cells are unique cells that can differentiate to produce more stem cells or other types of cells and can divide both symmetrically (to produce daughter cells with the same fate) and asymmetrically (to produce one daughter cell that retains stem cell potential and one that differentiates). The mechanisms that control the outcome of stem cell divisions have been the focus of many studies; however, they remain mainly unknown. Here, we have analyzed these mechanisms in murine hematopoietic stem cells (HSCs) by directly comparing the epigenetic signature, the transcriptome, and the function of the two daughter cells stemming from the first division of either a young or an aged HSC. We observe that, while young HSCs divide mainly asymmetrically, aged HSCs divide primarily symmetrically. We find that the mode of division is tightly linked to stem cell polarity and is regulated by the activity level of the small RhoGTPase cell division control protein 42 (Cdc42). In addition, we show that the potential of daughter cells is further linked to the amount of the epigenetic mark H4K16ac and also to the amount of open chromatin allocated to a daughter cell, but it is not linked to its transcriptome. In summary, our study suggests that HSC polarity linked to Cdc42 activity drives the mode of division, while epigenetic mechanisms determine the functional outcome of the stem cell division.
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