Depletion of tet2 results in age-dependent changes in DNA methylation and gene expression in a zebrafish model of myelodysplastic syndrome
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE238176 | GEO | 2023/10/01
REPOSITORIES: GEO
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Project description:Myelodysplastic Syndrome (MDS) is a heterogenous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias and dysplasia. The gene encoding Ten-ele¬ven translocation 2 (TET2), a dioxygenase enzyme that catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine, is a recurrently mutated tumor suppressor gene in MDS and other myeloid malignancies. Previously, we reported a stable zebrafish line with a loss-of-function mutation in the tet2 gene. The tet2m/m mutant zebrafish developed a pre-MDS state with kidney marrow dysplasia but normal circulating blood counts by 11 months of age and accompanying anemia signifying the onset of MDS by 24 months of age. In the current study, we collected progenitor cells from the kidney marrows of the adult tet2m/m and tet2wt/wt fish at 4 and 15 months of age and performed enhanced reduced representation of bisulphite sequencing (ERRBS) and bulk RNA-seq to measure changes in DNA methylation and gene expression of HSPCs. A global increase in DNA methylation of gene promoter regions and CpG islands was observed in tet2m/m HSPCs at 4 months of age when compared to the wildtype. Further, hypermethylated genes were significantly enriched for targets of SUZ12 and MTF2 - involved in polycomb repressive complex 2 (PRC2). However, between 4 and 15 months of age, however, we observed a paradoxical global decrease in DNA methylation in tet2m/m HSPCs. Gene expression analysis identified upregulation of genes associated mTORC1 signaling and interferon gamma and alpha response in tet2m/m HSPCs at 4 months of age when compared to the wildtype. Downregulated genes in HSPCs of tet2 mutant fish at 4 months of age were enriched for cell cycle regulation, heme metabolism, and IL2/STAT5 signaling, possibly related to increased self-renewal and clonal advantage in HSPCs with tet2 loss of function. Finally, there was an overall inverse correlation between overall increased promoter methylation and gene expression.
2023-10-01 | GSE238174 | GEO
Project description:Myelodysplastic Syndrome (MDS) is a heterogenous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias and dysplasia. The gene encoding Ten-ele¬ven translocation 2 (TET2), a dioxygenase enzyme that catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine, is a recurrently mutated tumor suppressor gene in MDS and other myeloid malignancies. Previously, we reported a stable zebrafish line with a loss-of-function mutation in the tet2 gene. The tet2m/m mutant zebrafish developed a pre-MDS state with kidney marrow dysplasia but normal circulating blood counts by 11 months of age and accompanying anemia signifying the onset of MDS by 24 months of age. In the current study, we collected progenitor cells from the kidney marrows of the adult tet2m/m and tet2wt/wt fish at 4 and 15 months of age and performed enhanced reduced representation of bisulphite sequencing (ERRBS) and bulk RNA-seq to measure changes in DNA methylation and gene expression of HSPCs. A global increase in DNA methylation of gene promoter regions and CpG islands was observed in tet2m/m HSPCs at 4 months of age when compared to the wildtype. Further, hypermethylated genes were significantly enriched for targets of SUZ12 and MTF2 - involved in polycomb repressive complex 2 (PRC2). However, between 4 and 15 months of age, however, we observed a paradoxical global decrease in DNA methylation in tet2m/m HSPCs. Gene expression analysis identified upregulation of genes associated mTORC1 signaling and interferon gamma and alpha response in tet2m/m HSPCs at 4 months of age when compared to the wildtype. Downregulated genes in HSPCs of tet2 mutant fish at 4 months of age were enriched for cell cycle regulation, heme metabolism, and IL2/STAT5 signaling, possibly related to increased self-renewal and clonal advantage in HSPCs with tet2 loss of function. Finally, there was an overall inverse correlation between overall increased promoter methylation and gene expression.
2023-10-01 | GSE238175 | GEO
Project description:The ten-eleven translocation 2 gene (TET2) encodes a member of the TET family of DNA methylcytosine oxidases that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to initiate the demethylation of DNA within genomic CpG islands. Somatic loss-of-function mutations of TET2 are frequently observed in human myelodysplastic syndrome (MDS), which is a clonal malignancy characterized by dysplastic changes of developing blood cell progenitors, leading to ineffective hematopoiesis. We used genome-editing technology to disrupt the zebrafish Tet2 catalytic domain. tet2(m/m) (homozygous for the mutation) zebrafish exhibited normal embryonic and larval hematopoiesis but developed progressive clonal myelodysplasia as they aged, culminating in myelodysplastic syndromes (MDS) at 24 months of age, with dysplasia of myeloid progenitor cells and anemia with abnormal circulating erythrocytes. The resultant tet2(m/m) mutant zebrafish lines show decreased levels of 5hmC in hematopoietic cells of the kidney marrow but not in other cell types, most likely reflecting the ability of other Tet family members to provide this enzymatic activity in nonhematopoietic tissues but not in hematopoietic cells. tet2(m/m) zebrafish are viable and fertile, providing an ideal model to dissect altered pathways in hematopoietic cells and, for small-molecule screens in embryos, to identify compounds with specific activity against tet2 mutant cells.
| S-EPMC4323485 | biostudies-literature
Project description:Depletion of tet2 results in age-dependent changes in DNA methylation and gene expression in a zebrafish model of myelodysplastic syndrome
| PRJNA998260 | ENA
Project description:Depletion of tet2 results in age-dependent changes in DNA methylation and gene expression in a zebrafish model of myelodysplastic syndrome [RNAseq]
| PRJNA998264 | ENA
Project description:Depletion of tet2 results in age-dependent changes in DNA methylation and gene expression in a zebrafish model of myelodysplastic syndrome [DNAmethylation]
| PRJNA998262 | ENA
Project description:Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders, representing high risk of progression to acute myeloid leukaemia, and frequently associated to somatic mutations, notably in the epigenetic regulator TET2. Natural Killer (NK) cells play a role in the anti-leukemic immune response via their cytolytic activity. Here we show that patients with MDS clones harbouring mutations in the TET2 gene are characterised by phenotypic defects in their circulating NK cells. Remarkably, NK cells and MDS clones from the same patient share the TET2 genotype, and the NK cells are characterised by increased methylation of genomic DNA and reduced expression of Killer Immunoglobulin-like receptors (KIR), perforin, and TNF-α. In vitro inhibition of TET2 in NK cells of healthy donors reduces their cytotoxicity, supporting its critical role in NK cell function. Conversely, NK cells from patients treated with azacytidine (#NCT02985190; https://clinicaltrials.gov/ ) show increased KIR and cytolytic protein expression, and IFN-γ production. Altogether, our findings show that, in addition to their oncogenic consequences in the myeloid cell subsets, TET2 mutations contribute to repressing NK-cell function in MDS patients.
| S-EPMC9898569 | biostudies-literature
Project description:Myelodysplastic syndrome (MDS), a largely incurable hematological malignancy, is derived from aberrant clonal hematopoietic stem/progenitor cells (HSPCs) that persist after conventional therapies. Defining the mechanisms underlying MDS HSPC maintenance is critical for developing MDS therapy. The deacetylase SIRT1 regulates stem cell proliferation, survival, and self-renewal by deacetylating downstream proteins. Here we show that SIRT1 protein levels were downregulated in MDS HSPCs. Genetic or pharmacological activation of SIRT1 inhibited MDS HSPC functions, whereas SIRT1 deficiency enhanced MDS HSPC self-renewal. Mechanistically, the inhibitory effects of SIRT1 were dependent on TET2, a safeguard against HSPC transformation. SIRT1 deacetylated TET2 at conserved lysine residues in its catalytic domain, enhancing TET2 activity. Our genome-wide analysis identified cancer-related genes regulated by the SIRT1/TET2 axis. SIRT1 activation also inhibited functions of MDS HSPCs from patients with TET2 heterozygous mutations. Altogether, our results indicate that restoring TET2 function through SIRT1 activation represents a promising means to target MDS HSPCs.
| S-EPMC6143172 | biostudies-literature
Project description:Aberrant innate immune signaling in myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cells (HSPCs) has been implicated as a driver of the development of MDS. We herein demonstrated that a prior stimulation with bacterial and viral products followed by loss of the Tet2 gene facilitated the development of MDS via up-regulating the target genes of the Elf1 transcription factor and remodeling the epigenome in hematopoietic stem cells (HSCs) in a manner that was dependent on Polo-like kinases (Plk) downstream of Tlr3/4-Trif signaling but did not increase genomic mutations. The pharmacological inhibition of Plk function or the knockdown of Elf1 expression was sufficient to prevent the epigenetic remodeling in HSCs and diminish the enhanced clonogenicity and the impaired erythropoiesis. Moreover, this Elf1-target signature was significantly enriched in MDS HSPCs in humans. Therefore, prior infection stress and the acquisition of a driver mutation remodeled the transcriptional and epigenetic landscapes and cellular functions in HSCs via the Trif-Plk-Elf1 axis, which promoted the development of MDS.
| S-EPMC10120406 | biostudies-literature
Project description:Tet methylcytosine dioxygenase2 gene (TET2) is one of the most frequently mutated gene in myeloid neoplasm, but the prognostic role of TET2 aberrations in myelodysplastic syndromes (MDS) remains unclear. Therefore, we performed a meta-analysis. Fourteen eligible studies with 1983 patients were included in this meta-analysis. Among these, 2 studies evaluated the impact that the TET2 expression level had on the prognosis. The combined hazard ratios (HR) estimated for overall survival (OS) was 1.00 (95%CI: 0.74 to 1.37; p=0.989) when comparing those with TET2 mutations with those without. Among the patients treated with hypomethylating agents (HMAs) or hematopoietic stem cell transplantation (HSCT), the pooled HR for OS was 1.02 (95% CI: 0.77-1.35, p=0.89) and 1.54 (95%CI: 0.69 to 3.44; p=0.29), respectively. We also conducted an analysis of the response rate to HMAs, and the OR was 1.73 (95%CI: 1.11 to 2.70; p=0.016). Additionally, subgroup analyses showed the pooled HR for OS was 0.93(95%CI: 0.44 to 1.98; P=0.849) in WHO-classified CMML patients and 1.02(95%CI: 1.02 to 3.46; p=0.042) in studies evaluated TET2 expression level. The analysis suggested TET2 mutations had no significant prognostic value on MDS. However, the response rates to HMAs were significantly different between those with and without TET2 mutations, and the low expression level of TET2 gene was significantly associated with a poor OS in MDS patients.
| S-EPMC5522146 | biostudies-other