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A zebrafish model of myelodysplastic syndrome produced through tet2 genomic editing.

ABSTRACT: 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.

SUBMITTER: Gjini E

PROVIDER: S-EPMC4323485 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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A zebrafish model of myelodysplastic syndrome produced through tet2 genomic editing.

Gjini Evisa E Mansour Marc R MR Sander Jeffry D JD Moritz Nadine N Nguyen Ashley T AT Kesarsing Michiel M Gans Emma E He Shuning S Chen Si S Ko Myunggon M Kuang You-Yi YY Yang Song S Zhou Yi Y Rodig Scott S Zon Leonard I LI Joung J Keith JK Rao Anjana A Look A Thomas AT

Molecular and cellular biology 20141215 5

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 use ...[more]

PMID: 25512612

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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.

Dataset Information

A zebrafish model of myelodysplastic syndrome produced through tet2 genomic editing.

Publications

A zebrafish model of myelodysplastic syndrome produced through tet2 genomic editing.

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