Tet Proteins Regulate Neutrophil Granulation in Zebrafish through Demethylation of socs3b mRNA

• Published in: Cell reports (Cambridge) 2021-01, Vol.34 (2), p.108632-108632, Article 108632
• Main Authors: Banks, Kelly M., Lan, Yahui, Evans, Todd
• Format: Article
• Language: English
• Subjects: Animals; cytokine; Demethylation; Dioxygenases - metabolism; epitranscriptomics; Granulation Tissue; methylation; mRNA stability; myelopoiesis; Neutrophils - metabolism; RNA - metabolism; Suppressor of Cytokine Signaling 3 Protein - metabolism; Zebrafish; Zebrafish Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108632

Tet proteins (Tet1/2/3) convert 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine (5hmC), initiating the process of active demethylation to regulate gene expression. Demethylation has been investigated primarily in the context of DNA, but recently Tet enzymes have also been shown to mediate demethylation of 5mC in RNA as an additional level of epitranscriptomic regulation. We analyzed compound tet2/3 mutant zebrafish and discovered a role for Tet enzymes in the maturation of primitive and definitive neutrophils during granulation. Transcript profiling showed dysregulation of cytokine signaling in tet mutant neutrophils, including upregulation of socs3b. We show that Tet normally demethylates socs3b mRNA during granulation, thereby destabilizing the transcript, leading to its downregulation. Failure of this process leads to accumulation of socs3b mRNA and repression of cytokine signaling at this crucial step of neutrophil maturation. This study provides further evidence for Tets as epitranscriptomic regulatory enzymes and implicates Tet2/3 in regulation of neutrophil maturation. [Display omitted] •Zebrafish with compound tet2/3 mutations show defects in neutrophil maturation•Defects are associated with altered cytokine signaling and increased socs3b mRNA•The socs3b mRNA rather than the gene itself is hypermethylated•The data further support Tets as epitranscriptomic regulatory proteins Tet proteins are known for removing or blocking DNA methylation. Banks et al. show that zebrafish mutant for tet2/3 have defects in maturation of primitive and definitive neutrophils. However, the phenotype is associated with hypermethylation of socs3b RNA, leading to enhanced socs3b RNA stability and a block in normal cytokine signaling.