A chromatin perspective on metabolic and genotoxic impacts on hematopoietic stem and progenitor cells
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Cellular and Molecular Life Sciences
REVIEW
A chromatin perspective on metabolic and genotoxic impacts on hematopoietic stem and progenitor cells Zhenhua Yang1 · Hao Jiang2 Received: 14 January 2020 / Revised: 17 March 2020 / Accepted: 6 April 2020 © Springer Nature Switzerland AG 2020
Abstract 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. Keywords Chromatin · Histone modifications · Demethylation · Hematopoietic stem cells · Metabolism · Genome integrity · DNA damage response
Introduction The mission of somatic stem cells is to maintain tissue homeostasis throughout the lifespan of an organism. To accomplish this mission, stem cells have two defining properties, self-renewal to replenish themselves and differentiation to give arise to cells of all lineages in the specific tissue. Hematopoietic stem cells (HSCs) provide a continuous supply of blood cells by strictly regulating self-renewal and balanced lineage differentiation through generating hematopoietic progenitor cells (HPCs) and further downstream cells. Blood disease can arise as a result of dysregulated * Zhenhua Yang [email protected] * Hao Jiang [email protected] 1
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
2
activities of HSCs and/or HPCs (HSPCs), as seen in bone marrow failure or hematologic malignancy [1]. Fate determination is thus probably the most pertinent question in stem cell biology. Chromatin is at the forefront of stem cell biology for two main reasons: (1) chromatin is the physiological substrate of transcription reaction and profoundly regulates gene expression including transcription and RNA splicing, and it is the gene expression profile of a cell that ultimately determines the cell to be still a stem cell or a daugh
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