Micronutrient supplementation affects transcriptional and epigenetic regulation of lipid metabolism in a dose-dependent manner

ABSTRACT

Micronutrients (vitamins and minerals) have been less well studied compared to macronutrients (fats, proteins, and carbohydrates) although they play important roles in growth, metabolism, and maintenance of tissues. Hence, there is growing interest to understand the influence of micronutrients across various aspects in nutritional research. In the last two decades, aquaculture feeds have been shifted to containing more plant-based materials to meet the increasing demand and maintain the sustainability in the industry. A recent whole life cycle feeding trial of Atlantic salmon (Salmo salar) with graded levels of micronutrient packages has concluded that the levels of several B-vitamins and microminerals need to be increased from the current recommendation levels for optimal growth and fish welfare when plant-based diets are used. Here, we show the effect of micronutrient supplementation on hepatic transcriptional and epigenetic regulation in a dose dependent manner. . Specifically, our aim is to reveal the mechanisms of altered cell metabolism, which results in improved growth performance by micronutrient surpluses, at gene expression and DNA methylation levels. Our results strongly indicate that micronutrient supplementation suppresses gene expression in lipid metabolism in a dose-dependent manner and broadly affects DNA methylation in cell-adhesion and cell-signalling. In particular, it increases DNA methylation levels on the acetyl-CoA carboxylase alpha promoter in a concentration-dependent manner, which further suggests that acetyl-CoA carboxylase alpha is an upstream epigenetic regulator controlling its downstream lipid biosynthesis activities. This study demonstrates a comprehensive analysis to reveal an important role of micronutrients in lipid metabolism through epigenetic control of gene expression.

KEYWORDS:

• Aquaculture
• atlantic salmon
• micronutrient
• DNA methylation
• epigenetics
• RRBS
• lipid metabolism
• steroid biosynthesis
• acetyl-CoA
• acetyl-CoA carboxylase alpha

Acknowledgments

We thank Amelie Nemc, Bekir Ergüner, and Christoph Bock for sequencing and advice on RRBS analysis, and Hui-Shan Tung and Eva Mykkeltvedt for DNA and RNA extraction at the Institute of Marine Research (Bergen, Norway). This work was supported by the European Commission under FP7 Integrated Project No. 288925, Advanced Research Initiatives for Nutrition & Aquaculture (ARRAINA); and by the Norwegian Research Council under project no: 267787 (NutrEpi).

Author contributions

K.H.S conceived and designed the genomic and epigenetic research. J.F.T. and D.R.T. conducted and designed the feeding trail. J.M.O.F., P.W. T.S. prepared RNA-seq and RRBS data. T.S., P.W., A.A., M.E. and K.H.S. analysed and interpreted data. T.S. drafted the manuscript. The authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability

Quality trimmed read data for both RNA-seq samples (PRJNA632591) and RRBS samples (PRJNA628740) have been uploaded to the Sequence Read Archive. As resources for further analyses, nine data sets – (i) DEGs, (ii) KEGG with DEGs, (iii) mapped CpGs (L2:L1), (iv) mapped CpGs (L3:L1), (v) DMGs, (vi) KEGG with DMGs (L2:L1), (vii) KEGG with DMGs (L3:L1), (viii) common DMGs, and (vi) DEGs with DMCs – have been uploaded to Figshare (DOI: 10.6084/m9.figshare.12481826; see Supplementary Tables 24-32 for data descriptions).

Supplementary materials

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the FP7 Ideas: European Research Council [288925]; The Research Council of Norway [267787].