LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells.
LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells.
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DOI：
10.1186/s13059-018-1557-3
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发表时间：
2018-11-07
期刊：
影响因子：
12.3
通讯作者：
Florian MC
中科院分区：
文献类型：
--
作者：
Grigoryan A;Guidi N;Senger K;Liehr T;Soller K;Marka G;Vollmer A;Markaki Y;Leonhardt H;Buske C;Lipka DB;Plass C;Zheng Y;Mulaw MA;Geiger H;Florian MC
随着年龄的增长，造血干细胞（HSC）功能的下降有助于衰老相关的免疫重塑和白血病的发病机制。衰老的造血干细胞表现出表观基因组的变化，如DNA甲基化、组蛋白甲基化和乙酰化景观的改变。我们之前通过H4K16ac的特定分布表明，衰老hsc中Cdc42的高活性与核内表观遗传极性或外极性的丧失之间存在相关性。在这里，我们发现并不是所有的组蛋白修饰都显示极性定位，H4K16ac数量的减少和外极性的丧失是衰老的hsc所特有的。增加H4K16ac水平不足以恢复衰老HSC的极性和恢复HSC功能。H4K16ac在造血干细胞衰老和年轻化过程中的变化与11号染色体结构的改变以及核体积和形状的改变有关。令人惊讶的是，通过利用敲除小鼠模型，我们证明Cdc42活性水平的增加与核包膜蛋白LaminA/C的抑制相关，而LaminA/C控制着衰老hsc中11号染色体的分布、H4K16ac极性以及核体积和形状。总的来说，我们的数据表明，衰老干细胞中染色质结构的变化是可逆的，通过降低Cdc42活性水平，揭示了一种意想不到的方法，可以从药理学上靶向LaminA/C表达，并恢复衰老hsc中表观遗传结构的改变。本文的在线版本（10.1186/s13059-018-1557-3）包含补充内容，仅供授权用户使用。
The decline of hematopoietic stem cell (HSC) function upon aging contributes to aging-associated immune remodeling and leukemia pathogenesis. Aged HSCs show changes to their epigenome, such as alterations in DNA methylation and histone methylation and acetylation landscapes. We previously showed a correlation between high Cdc42 activity in aged HSCs and the loss of intranuclear epigenetic polarity, or epipolarity, as indicated by the specific distribution of H4K16ac. Here, we show that not all histone modifications display a polar localization and that a reduction in H4K16ac amount and loss of epipolarity are specific to aged HSCs. Increasing the levels of H4K16ac is not sufficient to restore polarity in aged HSCs and the restoration of HSC function. The changes in H4K16ac upon aging and rejuvenation of HSCs are correlated with a change in chromosome 11 architecture and alterations in nuclear volume and shape. Surprisingly, by taking advantage of knockout mouse models, we demonstrate that increased Cdc42 activity levels correlate with the repression of the nuclear envelope protein LaminA/C, which controls chromosome 11 distribution, H4K16ac polarity, and nuclear volume and shape in aged HSCs. Collectively, our data show that chromatin architecture changes in aged stem cells are reversible by decreasing the levels of Cdc42 activity, revealing an unanticipated way to pharmacologically target LaminA/C expression and revert alterations of the epigenetic architecture in aged HSCs. The online version of this article (10.1186/s13059-018-1557-3) contains supplementary material, which is available to authorized users.
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影响因子：
23.9
作者：
Florian, Maria Carolina;Doerr, Karin;Niebel, Anja;Daria, Deidre;Schrezenmeier, Hubert;Rojewski, Markus;Filippi, Marie-Dominique;Hasenberg, Anja;Gunzer, Matthias;Scharffetter-Kochanek, Karin;Zheng, Yi;Geiger, Hartmut
通讯作者：
Geiger, Hartmut
影响因子：
64.8
作者：
Chen JY;Miyanishi M;Wang SK;Yamazaki S;Sinha R;Kao KS;Seita J;Sahoo D;Nakauchi H;Weissman IL
通讯作者：
Weissman IL
影响因子：
64.5
作者：
Adolfsson, J;Månsson, R;Jacobsen, SEW
通讯作者：
Jacobsen, SEW
影响因子：
9.8
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
通讯作者：
Geiger H
影响因子：
13.6
作者：
Akunuru S;Geiger H
通讯作者：
Geiger H