Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, 10016, USA.
Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, 10016, USA.
Epigenetics Chromatin. 2024 Jan 23;17(1):2. doi: 10.1186/s13072-024-00526-w.
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 G 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.
血液平衡需要每天产生数百万个终末分化的效应细胞，这些细胞都源自造血干细胞（HSCs）。HSCs 数量稀少，具有独特的自我更新和多能性，这依赖于它们通过尚未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可能导致骨髓衰竭或恶性肿瘤。特别是，将细胞周期重新进入与 HSCs 中细胞命运决定联系起来的分子机制仍然难以捉摸。先前的研究已经确定染色质协调是胚胎干细胞分化的关键调节剂。
在这里，我们利用染色质相关 Sin3B 蛋白的遗传失活来操纵细胞周期控制，发现 HSCs 中的染色质可及性和细胞周期进程失调。对 Sin3B 失活的造血干细胞和祖细胞（HSPC）进行单细胞转录谱分析显示，细胞周期 G 期的异常进展与特定信号通路的参与相关，包括细胞黏附分子和 LT-HSCs 中干扰素信号通路的异常表达。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，这表明细胞周期进展可能决定了 HSC 分化的启动。
我们的研究结果提供了新的见解，即通过调节染色质特征，将受控的细胞周期进程作为 HSC 谱系决定的潜在调节剂。
