Chromatin accessibility and cell cycle progression are controlled by the HDAC-associated Sin3B protein in murine hematopoietic stem cells.
Chromatin accessibility and cell cycle progression are controlled by the HDAC-associated Sin3B protein in murine hematopoietic stem cells.
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DOI：
10.1186/s13072-024-00526-w
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发表时间：
2024-01-23
影响因子：
3.9
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中科院分区：
文献类型：
--
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血液稳态需要每天产生数百万个终末分化效应细胞，这些细胞全部源自造血干细胞 (HSC)。 HSC 很罕见，并表现出独特的自我更新和多能特性，这取决于它们通过不明确的过程维持静止的能力。细胞周期进程的控制缺陷最终会导致骨髓衰竭或恶性肿瘤。特别是，HSC 中将细胞周期重新进入与细胞命运承诺联系起来的分子机制仍然难以捉摸。先前的研究已确定染色质协调是胚胎干细胞分化的关键调节因子。在这里，我们利用染色质相关 Sin3B 蛋白的基因失活来操纵细胞周期控制，并发现 HSC 中染色质可及性和细胞周期进展失调。 Sin3B 失活的造血干细胞和祖细胞 (HSPC) 的单细胞转录谱揭示了细胞周期 G1 期的异常进展，这与特定信号通路的参与相关，包括细胞粘附分子的异常表达和 LT-HSC 中的干扰素信号传导程序。此外，我们发现了控制 HSC 分化的基因组元件的 Sin3B 依赖性可及性，这表明细胞周期进程可能决定 HSC 分化的启动。我们的研究结果为通过调节染色质特征来控制细胞周期进程作为 HSC 谱系定型的潜在调节剂提供了新的见解。在线版本包含可在 10.1186/s13072-024-00526-w 获取的补充材料。
Blood homeostasis requires the daily production of millions of terminally differentiated effector cells that all originate from hematopoietic stem cells (HSCs). HSCs are rare and exhibit unique self-renewal and multipotent properties, which depend on their ability to maintain quiescence through ill-defined processes. Defective control of cell cycle progression can eventually lead to bone marrow failure or malignancy. In particular, the molecular mechanisms tying cell cycle re-entry to cell fate commitment in HSCs remain elusive. Previous studies have identified chromatin coordination as a key regulator of differentiation in embryonic stem cells. Here, we utilized genetic inactivation of the chromatin-associated Sin3B protein to manipulate cell cycle control and found dysregulated chromatin accessibility and cell cycle progression in HSCs. Single cell transcriptional profiling of hematopoietic stem and progenitor cells (HSPCs) inactivated for Sin3B reveals aberrant progression through the G1 phase of the cell cycle, which correlates with the engagement of specific signaling pathways, including aberrant expression of cell adhesion molecules and the interferon signaling program in LT-HSCs. In addition, we uncover the Sin3B-dependent accessibility of genomic elements controlling HSC differentiation, which points to cell cycle progression possibly dictating the priming of HSCs for differentiation. Our findings provide new insights into controlled cell cycle progression as a potential regulator of HSC lineage commitment through the modulation of chromatin features. The online version contains supplementary material available at 10.1186/s13072-024-00526-w.
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影响因子：
4
作者：
Calder, Ashley;Roth-Albin, Ivana;Draper, Jonathan S.
通讯作者：
Draper, Jonathan S.
DOI：
10.1126/science.1256271
发表时间：
2014-08-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lara-Astiaso D;Weiner A;Lorenzo-Vivas E;Zaretsky I;Jaitin DA;David E;Keren-Shaul H;Mildner A;Winter D;Jung S;Friedman N;Amit I
通讯作者：
Amit I
影响因子：
8.8
作者：
Bainor, Anthony J.;Saini, Siddharth;David, Gregory
通讯作者：
David, Gregory
影响因子：
8
作者：
DiMauro, T.;Cantor, D. J.;David, G.
通讯作者：
David, G.
影响因子：
23.9
作者：
Laurenti, Elisa;Frelin, Catherine;Xie, Stephanie;Ferrari, Robin;Dunant, Cyrille F.;Zandi, Sasan;Neumann, Andrea;Plumb, Ian;Doulatov, Sergei;Chen, Jing;April, Craig;Fan, Jian-Bing;Iscove, Norman;Dick, John E.
通讯作者：
Dick, John E.