School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Cell Mol Life Sci. 2020 Oct;77(20):4031-4047. doi: 10.1007/s00018-020-03522-x. Epub 2020 Apr 21.
Fate determination in self-renewal and differentiation of hematopoietic stem and progenitor cells (HSCs and HPCs) is ultimately controlled by gene expression, which is profoundly influenced by the global and local chromatin state. Cellular metabolism directly influences the chromatin state through the dynamic regulation of the enzymatic activities that modify DNA and histones, but also generates genotoxic metabolites that can damage DNA and thus pose threat to the genome integrity. On the other hand, mechanisms modulating the chromatin state impact metabolism by regulating the expression and activities of key metabolic enzymes. Moreover, through regulating either DNA damage response directly or expression of genes involved in this process, chromatin modulators play active and crucial roles in guarding the genome integrity, breaching of which results in defective HSPC function. Therefore, HSPC function is regulated by the dynamic and two-way interactions between metabolism and chromatin. Here, we review recent advances that provide a chromatin perspective on the major impacts the metabolic and genotoxic factors can have on HSPC function and fate determination.
造血干细胞和祖细胞（HSCs 和 HPCs）的自我更新和分化中的命运决定最终受基因表达控制，而基因表达又受到染色质状态的全局和局部的深刻影响。细胞代谢通过动态调节修饰 DNA 和组蛋白的酶活性直接影响染色质状态，但也会产生遗传毒性代谢物，从而损害 DNA，从而对基因组完整性构成威胁。另一方面，调节染色质状态的机制通过调节关键代谢酶的表达和活性来影响代谢。此外，染色质调节剂通过直接调节 DNA 损伤反应或参与该过程的基因的表达，在保护基因组完整性方面发挥着积极和关键的作用，因为基因组完整性的破坏会导致 HSPC 功能缺陷。因此，HSPC 功能受到代谢和染色质之间的动态和双向相互作用的调节。在这里，我们回顾了最近的进展，这些进展从染色质的角度提供了对代谢和遗传毒性因素对 HSPC 功能和命运决定的主要影响的认识。
