Threonine dehydrogenase regulates neutrophil homeostasis but not H3K4me3 levels in zebrafish

• Published in: The FEBS journal Vol. 291; no. 15; pp. 3367 - 3383
• Main Authors: Li, Ning‐Zhe, Wang, Zi‐Xuan, Zhang, Fan, Feng, Chang‐Zhou, Chen, Yi, Liu, Dian‐Jia, Chen, Shu‐Bei, Jin, Yi, Zhang, Yuan‐Liang, Xie, Yin‐Yin, Huang, Qiu‐Hua, Wang, Lan, Li, Bing, Sun, Xiao‐Jian
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.08.2024
• Subjects: acetyl coenzyme A; adults; Alcohol Oxidoreductases - genetics; Alcohol Oxidoreductases - metabolism; Amino acids; Animal models; Animals; biogenesis; Cell fate; Chain branching; Danio rerio; Dehydrogenase; Dehydrogenases; Dietary supplements; Drug metabolism; drugs; Embryo cells; Enzymatic activity; enzyme activity; Epigenetics; glucose; Hematopoiesis; Hematopoiesis - genetics; Hemopoiesis; Histone H3; Histones; Histones - genetics; Histones - metabolism; Homeostasis; Immune response; In vivo methods and tests; kidneys; Leukocyte migration; Leukocytes (neutrophilic); Lysine; Metabolism; Methylation; Mice; mitochondria; Myelopoiesis; neutrophil; Neutrophils; Neutrophils - metabolism; Nutrients; Nutrition; Nutrition assessment; oxidoreductases; Phenotypes; Pyruvic acid; Stem cells; Threonine; threonine dehydrogenase; threonine metabolism; trimethylation of histone H3 lysine 4; Zebrafish; Zebrafish - genetics; Zebrafish - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; threonine dehydrogenase; zebrafish; threonine metabolism; neutrophil; trimethylation of histone H3 lysine 4
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.17138

l‐threonine dehydrogenase (Tdh) is an enzyme that links threonine metabolism to epigenetic modifications and mitochondria biogenesis. In vitro studies show that it is critical for the regulation of trimethylation of histone H3 lysine 4 (H3K4me3) levels and cell fate determination of mouse embryonic stem cells (mESCs). However, whether Tdh regulates a developmental process in vivo and, if it does, whether it also primarily regulates H3K4me3 levels in this process as it does in mESCs, remains elusive. Here, we revealed that, in zebrafish hematopoiesis, tdh is preferentially expressed in neutrophils. Knockout of tdh causes a decrease in neutrophil number and slightly suppresses their acute injury‐induced migration, but, unlike the mESCs, the level of H3K4me3 is not evidently reduced in neutrophils sorted from the kidney marrow of adult tdh‐null zebrafish. These phenotypes are dependent on the enzymatic activity of Tdh. Importantly, a soluble supplement of nutrients that are able to fuel the acetyl‐CoA pool, such as pyruvate, glucose and branched‐chain amino acids, is sufficient to rescue the reduction in neutrophils caused by tdh deletion. In summary, our study presents evidence for the functional requirement of Tdh‐mediated threonine metabolism in a developmental process in vivo. It also provides an animal model for investigating the nutritional regulation of myelopoiesis and immune response, as well as a useful tool for high‐throughput drug/nutrition screening. Amino acid catabolism regulates many biological processes. L‐threonine dehydrogenase (Tdh) is an enzyme that links threonine metabolism to epigenetic modifications and mitochondria biogenesis. In mammalian systems, Tdh is important for embryonic stem cell fate decisions through a mechanism associated with histone H3 lysine 4 trimethylation (H3K4me3). Here, we show that in the zebrafish hematopoietic system, Tdh regulates neutrophil homeostasis, and that this regulation is largely dependent on acetyl‐CoA production but not H3K4me3, providing evidence of the functional requirement of Tdh‐mediated threonine metabolism in a developmental process. Our study also provides a useful tool for zebrafish‐based high‐throughput drug/nutrition screening.