Hexokinase 3 enhances myeloid cell survival via non-glycolytic functions
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ABSTRACT:
PROVIDER: PRJNA809305 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18099966_1.fastq.gz | Fastqsanger.gz | |||
| SRR18099966_2.fastq.gz | Fastqsanger.gz | |||
| SRR18099967_1.fastq.gz | Fastqsanger.gz | |||
| SRR18099967_2.fastq.gz | Fastqsanger.gz | |||
| SRR18099968_1.fastq.gz | Fastqsanger.gz |
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Project description:The family of hexokinases (HKs) catalyzes the first step of glycolysis, the ATP-dependent phosphorylation of glucose to glucose-6-phosphate. While HK1 and HK2 are ubiquitously expressed, the less well-studied HK3 is primarily expressed in hematopoietic cells and tissues and is highly upregulated during terminal differentiation of some acute myeloid leukemia (AML) cell line models. Here we show that expression of HK3 is predominantly originating from myeloid cells and that the upregulation of this glycolytic enzyme is not restricted to differentiation of leukemic cells but also occurs during ex vivo myeloid differentiation of healthy CD34+ hematopoietic stem and progenitor cells. Within the hematopoietic system, we show that HK3 is predominantly expressed in cells of myeloid origin. CRISPR/Cas9 mediated gene disruption revealed that loss of HK3 has no effect on glycolytic activity in AML cell lines while knocking out HK2 significantly reduced basal glycolysis and glycolytic capacity. Instead, loss of HK3 but not HK2 led to increased sensitivity to ATRA-induced cell death in AML cell lines. We found that HK3 knockout (HK3-null) AML cells showed an accumulation of reactive oxygen species (ROS) as well as DNA damage during ATRA-induced differentiation. RNA sequencing analysis confirmed pathway enrichment for programmed cell death, oxidative stress, and DNA damage response in HK3-null AML cells. These signatures were confirmed in ATAC sequencing, showing that loss of HK3 leads to changes in chromatin configuration and increases the accessibility of genes involved in apoptosis and stress response. Through isoform-specific pulldowns, we furthermore identified a direct interaction between HK3 and the proapoptotic BCL-2 family member BIM, which has previously been shown to shorten myeloid life span. Our findings provide evidence that HK3 is dispensable for glycolytic activity in AML cells while promoting cell survival, possibly through direct interaction with the BH3-only protein BIM during ATRA-induced neutrophil differentiation.
| S-EPMC9091226 | biostudies-literature
Project description:Purpose: The goal was to compare transcriptome profiles of HL60 HK3-null and Cas9 expressing control cells treated with either ATRA or DMSO using RNA sequencing. In addition, to find accessible DNA regions by probing open chromatin with hyperactive mutant Tn5 Transposase using ATAC sequencing. Methods: HL60 HK3-null and Cas9 expressing control cells were treated with 1µM of ATRA or DMSO (0.01%) for 36h. Treated cells were then harvested for RNA-Seq and ATAC-Seq analysis. Results: We mapped sequence reads per sample to the human genome (GRCh38 - hg38) and identified differentially expressed transcripts as well as open chromatin peaks in AML HL60 HK3-null and Cas9 expressing cells upon treatment with ATRA or DMSO as control. Differentially expressed genes, were identified with a fold change ≥1.5 and FDR p-value <0.05. Conclusions: Our results show that HK3 knockout (HK3-null) AML cells had an accumulation of reactive oxygen species (ROS) as well as DNA damage during ATRA-induced differentiation. RNA sequencing analysis confirmed pathway enrichment for programmed cell death, oxidative stress and DNA damage response in HK3-null AML cells. These signatures were confirmed in ATAC sequencing, showing that loss of HK3 leads to changes in chromatin configuration and increases accessibility of genes involved in apoptosis and stress response.
2024-08-31 | GSE197164 | GEO
Project description:Fat graft survival requires metabolic reprogramming towards glycolytic pathway
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Project description:CRISPR/Cas9 screens reveal that hexokinase 2 enhances cancer stemness and tumorigenicity
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Project description:study of nucleotide sequence of hexokinase gene
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Project description:Background: The mechanisms underlying fat graft survival are poorly understood. Here, we performed unbiased transcriptomics analysis of mouse fat graft model to find out the molecular mechanism of free fat graft survival. Methods: We conducted RNA-sequencing (RNA-seq) analysis of mouse free subcutaneous fat graft model at day 3 and 7 following grafting (n=5). High-throughput sequencing was performed as paired-end using NovaSeq6000 (Illumina, CA, USA). The calculated transcripts per million (TPM) values were processed for principal component analysis (PCA), unsupervised hierarchically clustered heat map generation, and Gene set enrichment analysis. Results: PCA and heat map data revealed global differences in the transcriptome of grafted fat when compared with non-graft control. The top meaningful up-regulated gene sets in the grafted fat were related to epithelial mesenchymal transition and hypoxia by day 3, and angiogenesis by day 7. Mechanistically, the glycolysis pathway was commonly upregulated in the grafted fat at day 3 (FDR q=0.012) and day 7 (FDR q=0.084). In subsequent experiments, pharmacological inhibition of glycolytic pathway in the grafted fat with 2-Deoxy-D-glucose (2-DG) significantly suppressed fat graft retention rates, both grossly and microscopically (n=5). Conclusions: Global transcriptome analysis and pharmacologic inhibition study revealed that free adipose tissue grafts undergo metabolic reprogramming towards glycolytic pathway. Whether targeting the pathway wound enhance graft survival rate remains to be investigated.
2024-06-01 | GSE203599 | GEO
Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).
2023-05-05 | GSE229153 | GEO
Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).
2023-05-05 | GSE229151 | GEO