TETs Regulate Proepicardial Cell Migration through Extracellular Matrix Organization during Zebrafish Cardiogenesis

Abstract

SUMMARY Ten-eleven translocation (Tet) enzymes (Tet1/2/3) mediate 5-methylcytosine (5mC) hydroxylation, which can facilitate DNA demethylation and thereby impact gene expression. Studied mostly for how mutant isoforms impact cancer, the normal roles for Tet enzymes during organogenesis are largely unknown. By analyzing compound mutant zebrafish, we discovered a requirement for Tet2/3 activity in the embryonic heart for recruitment of epicardial progenitors, associated with development of the atrial-ventricular canal (AVC). Through a combination of methylation, hydroxymethylation, and transcript profiling, the genes encoding the activin A subunit Inhbaa (in endocardium) and Sox9b (in myocardium) were implicated as demethylation targets of Tet2/3 and critical for organization of AVC-localized extracellular matrix (ECM), facilitating migration of epicardial progenitors onto the developing heart tube. This study elucidates essential DNA demethylation modifications that govern gene expression changes during cardiac development with striking temporal and lineage specificities, highlighting complex interactions in multiple cell populations during development of the vertebrate heart.

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

“…In zebrafish, hematopoiesis takes place in three waves: an initial primitive wave with spatially segregated myeloid (neutrophil, mast cell, and macrophage) and erythroid cells; a transient wave where erythromyeloid progenitors (EMPs) give rise to red blood cells, neutrophils, and mast cells; and, finally, the definitive wave, where HSCs are specified and give rise to all lineages including lymphoid cells from 5 days post fertilization (dpf) through adulthood ( de Jong and Zon, 2005 ; Dobson et al, 2008 ). To explore functions for Tet proteins in neutrophils, we used a tet2/3 double-mutant ( tet2/3 DM ) zebrafish model ( Lan et al, 2019 ; Li et al, 2015 ). Previous work showed that Tet2 and Tet3 are the primary dioxygenases during zebrafish embryogenesis, with tet2/3 DM embryos essentially devoid of 5hmC ( Li et al, 2015 ).…”

LINC-PINT Suppresses the Aggressiveness of Thyroid Cancer by Downregulating miR-767-5p to Induce TET2 Expression

“…The ten-eleven translocation (TET) family comprising three members (TET1, TET2, and TET3) is an important epigenetic modifier. 6 TET proteins are capable of converting 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC), consequently leading to DNA demethylation. 7 Accumulating evidence has linked TET proteins to tumorigenesis.…”

Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy

“…Additionally, ten‐eleven translocation, or TET , methylation modifying genes have been established as essential regulators of cardiac development and also potential implications in the formation of cardiac fibrosis. TET1 has an essential role modifying DNA during cardiac development, and its absence leads to perinatal lethality (Lan et al, 2019). Dams showed a decrease in mRNA levels when exposed to adverse maternal stressors, which has been tied to cardiac fibrosis and a suspected early‐life alteration of TET expression that in turn alters fibrotic susceptibility (Spearman, Ke, Fu, Lane, & Majnik, 2018).…”