C Simner1, B Novakovic2, K A Lillycrop3, C G Bell4, N C Harvey5, C Cooper6, R Saffery2, R M Lewis1, J K Cleal7. 1. The Institute of Developmental Sciences, University of Southampton, UK. 2. Cancer and Disease Epigenetics, Murdoch Children's Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia. 3. The Institute of Developmental Sciences, University of Southampton, UK; Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton SO17 1BJ, UK. 4. The Institute of Developmental Sciences, University of Southampton, UK; MRC Lifecourse Epidemiology Unit, University of Southampton, UK. 5. MRC Lifecourse Epidemiology Unit, University of Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospital Southampton, NHS Foundation Trust, UK. 6. MRC Lifecourse Epidemiology Unit, University of Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospital Southampton, NHS Foundation Trust, UK; NIHR Oxford Musculoskeletal Biomedical Research Unit, University of Oxford, UK. 7. The Institute of Developmental Sciences, University of Southampton, UK. Electronic address: j.cleal@soton.ac.uk.
Abstract
INTRODUCTION: Placental transfer of amino acids via amino acid transporters is essential for fetal growth. Little is known about the epigenetic regulation of amino acid transporters in placenta. This study investigates the DNA methylation status of amino acid transporters and their expression across gestation in human placenta. METHODS: BeWo cells were treated with 5-aza-2'-deoxycytidine to inhibit methylation and assess the effects on amino acid transporter gene expression. The DNA methylation levels of amino acid transporter genes in human placenta were determined across gestation using DNA methylation array data. Placental amino acid transporter gene expression across gestation was also analysed using data from publically available Gene Expression Omnibus data sets. The expression levels of these transporters at term were established using RNA sequencing data. RESULTS: Inhibition of DNA methylation in BeWo cells demonstrated that expression of specific amino acid transporters can be inversely associated with DNA methylation. Amino acid transporters expressed in term placenta generally showed low levels of promoter DNA methylation. Transporters with little or no expression in term placenta tended to be more highly methylated at gene promoter regions. The transporter genes SLC1A2, SLC1A3, SLC1A4, SLC7A5, SLC7A11 and SLC7A10 had significant changes in enhancer DNA methylation across gestation, as well as gene expression changes across gestation. CONCLUSION: This study implicates DNA methylation in the regulation of amino acid transporter gene expression. However, in human placenta, DNA methylation of these genes remains low across gestation and does not always play an obvious role in regulating gene expression, despite clear evidence for differential expression as gestation proceeds.
INTRODUCTION: Placental transfer of amino acids via amino acid transporters is essential for fetal growth. Little is known about the epigenetic regulation of amino acid transporters in placenta. This study investigates the DNA methylation status of amino acid transporters and their expression across gestation in human placenta. METHODS: BeWo cells were treated with 5-aza-2'-deoxycytidine to inhibit methylation and assess the effects on amino acid transporter gene expression. The DNA methylation levels of amino acid transporter genes in human placenta were determined across gestation using DNA methylation array data. Placental amino acid transporter gene expression across gestation was also analysed using data from publically available Gene Expression Omnibus data sets. The expression levels of these transporters at term were established using RNA sequencing data. RESULTS: Inhibition of DNA methylation in BeWo cells demonstrated that expression of specific amino acid transporters can be inversely associated with DNA methylation. Amino acid transporters expressed in term placenta generally showed low levels of promoter DNA methylation. Transporters with little or no expression in term placenta tended to be more highly methylated at gene promoter regions. The transporter genes SLC1A2, SLC1A3, SLC1A4, SLC7A5, SLC7A11 and SLC7A10 had significant changes in enhancer DNA methylation across gestation, as well as gene expression changes across gestation. CONCLUSION: This study implicates DNA methylation in the regulation of amino acid transporter gene expression. However, in human placenta, DNA methylation of these genes remains low across gestation and does not always play an obvious role in regulating gene expression, despite clear evidence for differential expression as gestation proceeds.
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