Defining Tet Enzyme Requirements In Normal Vertebrate Development And Hematopoiesis

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Abstract

The ten-eleven translocation proteins TET1, TET2, and TET3 mediate oxidation of the modified base 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) through an iterative process. Oxidation of 5mC has been suggested to play the first step in DNA demethylation pathways. However, the functions of TET proteins in promoting vertebrate development and differentiation have not been fully defined. To systematically assess the requirements for TET proteins during development, we mutated the zebrafish orthologs of TET1, TET2, and TET3, and examined single, double and triple mutant genotypes. Using these mutant lines, we identified Tet2 and Tet3 as the major 5-methylcytosine dioxygenases in the zebrafish embryo. In addition, we have uncovered overlapping requirements for Tet2 and Tet3 in hematopoietic stem cell (HSC) development. Our results identify Tet2 and Tet3 as early regulators of the notch signaling required for induction of the hematopoietic transcription factor program in the hemogenic endothelium. These studies have also revealed a potential link between inflammatory signaling from the primitive hematopoietic system and defective notch signaling in tet2/3 mutants. Further study revealed that enhanced Tet1 activity could compensate the loss for Tet2/3 during HSC emergence, providing evidence that members of TET family behave similarly and can act interchangeably when expressed at sufficient levels. Lastly, we discuss applications of the tet2/3DM platform to identifying novel regulators of TET proteins. Collectively, this research defines essential, overlapping functions for TET proteins during embryonic development and uncovers a requirement for 5hmC in regulating HSC emergence. Additionally, the findings, as well as the tet2/3 double mutant larvae we generated, hold great promise to facilitate the study of blood cancer treatment.

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2018
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Epigenetics; Hematopoietic stem cell; hydroxymethylcytosine; TET; zebrafish
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Cell & Developmental Biology
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Doctor of Philosophy
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Government Document
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Attribution-NonCommercial-NoDerivatives 4.0 International
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dissertation or thesis
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