Identification of Regulatory Networks in HSCs and Their Immediate Progeny via Integrated Proteome, Transcriptome, and DNA Methylome Analysis

Cabezas-Wallscheid, Nina; Klimmeck, Daniel; Hansson, Jenny; Lipka, Daniel B.; Reyes, Alejandro; Wang, Qi; Weichenhan, Dieter; Lier, Amelie; Paleske, Lisa von; Renders, Simon; Wünsche, Peer; Zeisberger, Petra; Brocks, David; Gu, Lei; Herrmann, Carl; Haas, Simon; Essers, Marieke; Brors, Benedikt; Eils, Roland; Huber, Wolfgang; Milsom, Michael D.; Plass, Christoph; Krijgsveld, Jeroen; Trumpp, Andreas

doi:10.1016/j.stem.2014.07.005

Cited by 462 publications

(552 citation statements)

References 82 publications

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“…In addition, HIF-1α is transcriptionally induced by Meis1, a transcription factor essential for HSC stemness [13]. Metabolome and flux analysis suggests that HSCs consume less oxygen and activate of glycolysis to a greater extent than their differentiated counterparts [10], an observation partly explained by relatively higher, HIF-1α-dependent expression of factors catalyzing anaerobic glycolysis [14]. HIF-1 also indirectly regulates glycolytic enzyme expression and cell survival through the autocrine Cripto/GRP78 pathway and through expression of Vegf [15].…”

Section: Regulation Of Anaerobic Glycolysis By Hif-1αmentioning

confidence: 99%

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Karigane

Takubo

2017

Int J Hematol

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organisms. HSPCs are composed of hematopoietic stem cells (HSCs) and several types of lineage-biased, but not fully committed, hematopoietic progenitor cells (HPCs). HSC capacities such as self-renewal and multilineage differentiation maintain the whole hematopoietic system over an organism's lifetime [1], and contribute to blood regeneration under stress condition, whereas HPCs reportedly function to maintain the supply of blood cells at steady state [2,3]. The surrounding BM microenvironment or "niche" determines HSC fate, namely its quiescence, symmetric/asymmetric division, differentiation, or migration potential, in both steady state and during stress. It is now evident that metabolic programs operating in HSCs play critical roles in maintaining hematopoietic homeostasis [4], often in response to BM niche signals [5]. Cellular pathways generate various metabolites through enzymatic activity that supplies material used as fuel, building blocks for other factors, or modulators of intra-or intercellular activities (Fig. 1). Despite the fact that numerous biochemical studies have addressed HSC metabolic regulation, numerous gaps in our knowledge of that regulation remain.Recently, novel means to fractionate metabolites using highly sensitive mass spectrometric technology [6] have dramatically facilitated metabolome analysis. These technologies reduce the need for high cell numbers and increase sensitivity of metabolite selection. As a result, metabolome analysis is feasible in rare cell populations such as HSCs. These analyses have revealed that metabolic programs play critical roles in maintaining stem cell "stemness" (Fig. 2). Here we review recent advances in the field of how metabolic changes regulate HSC dynamics under quiescence, proliferation, and differentiation from the viewpoint of each pathway. In addition to the normal HSC system, we also review activity of leukemia-related metabolic pathways, tumor-associated metabolites (oncometabolites), and Abstract Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

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Section: Regulation Of Anaerobic Glycolysis By Hif-1αmentioning

confidence: 99%

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Karigane

Takubo

2017

Int J Hematol

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“…This finding is in line with other studies using genome-wide methylation analyses along hematopoietic differentiation, which have shown a gradual gain of methylation during the hematopoietic differentiation process. 45 We identified H2afy2 as the top candidate target gene that was found to be both differentially methylated and among the top differentially expressed genes. Although, in this case, lower methylation levels correlated with lower gene expression levels for H2afy2, this observation is fully compatible with findings from other studies comparing gene expression levels and methylation levels on the global scale, where the classical anti-correlation can be observed on average, while there are also many DMRs that seem to be positively correlated with gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Although, in this case, lower methylation levels correlated with lower gene expression levels for H2afy2, this observation is fully compatible with findings from other studies comparing gene expression levels and methylation levels on the global scale, where the classical anti-correlation can be observed on average, while there are also many DMRs that seem to be positively correlated with gene expression. 45,46 Another possible explanation for this observation would be that the promoter hypomethylation of H2afy2 is a secondary adaptive effect by which the cells try to counteract the Plcγ1-associated downregulation of H2afy2 by hypomethylation of the promoter region, which then actually leads to a more transcriptionally permissive promoter state. The H2afy2 gene encodes for the histone variant mH2A2.…”

Section: Discussionmentioning

confidence: 99%

Epo-induced erythroid maturation is dependent on Plcγ1 signaling

et al. 2014

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Erythropoiesis is a tightly regulated process. Development of red blood cells occurs through differentiation of hematopoietic stem cells (HSCs) into more committed progenitors and finally into erythrocytes. Binding of erythropoietin (Epo) to its receptor (EpoR) is required for erythropoiesis as it promotes survival and late maturation of erythroid progenitors. In vivo and in vitro studies have highlighted the requirement of EpoR signaling through Janus kinase 2 (Jak2) tyrosine kinase and Stat5a/b as a central pathway. Here, we demonstrate that phospholipase C gamma 1 (Plcγ1) is activated downstream of EpoR-Jak2 independently of Stat5. Plcγ1-deficient pro-erythroblasts and erythroid progenitors exhibited strong impairment in differentiation and colony-forming potential. In vivo, suppression of Plcγ1 in immunophenotypically defined HSCs (Lin − Sca1 + KIT + CD48 − CD150 + ) severely reduced erythroid development. To identify Plcγ1 effector molecules involved in regulation of erythroid differentiation, we assessed changes occurring at the global transcriptional and DNA methylation level after inactivation of Plcγ1. The top common downstream effector was H2afy2, which encodes for the histone variant macroH2A2 (mH2A2). Inactivation of mH2A2 expression recapitulated the effects of Plcγ1 depletion on erythroid maturation. Taken together, our findings identify Plcγ1 and its downstream target mH2A2, as a 'non-canonical' Epo signaling pathway essential for erythroid differentiation.

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“…During normal hematopoietic differentiation, DNA methylation levels have been shown to both increase and decrease as hematopoietic stem cell (HSC) lineage specification progresses. [1][2][3] Recent studies of DNA methylation in hematopoietic stem and progenitor (HSPC) populations have elucidated finely tuned methylation changes taking place during differentiation, as well as identified some of the key regulators and drivers of this epigenetic process. [1][2][3][4] Major questions remain, however, regarding the relationship between DNA methylation status, including location in the genome (intron, exon, promoter, intergenic, etc.…”

mentioning

confidence: 99%

“…), and the resultant effect on overall gene expression. Following up on their recent generation and analysis of DNA methylomes in murine HSCs and 4 closely related multipotent progenitor populations (MPPs) using tagmentation-based whole genome bisulfite sequencing (TWGBS), 1 Lipka et al further categorize the molecular landscape changes in HSPCs during the very early stages of HSC differentiation. 5 They found a number of epigenetic changes that were inversely correlated with gene expression during HSPC differentiation ( Fig.…”

mentioning

confidence: 99%