Abstract
Wharton’s jelly-derived Mesenchymal Stem Cells (MSCs) isolated from newborns with intrauterine fetal growth restriction were previously shown to exert anabolic features including insulin hypersensitivity. Here, we extend these observations and demonstrate that MSCs from small for gestational age (SGA) individuals have decreased mitochondrial oxygen consumption rates. Comparing normally grown and SGA MSCs using next generation sequencing studies, we measured global transcriptomic and epigenetic profiles and identified E2F1 as an over-expressed transcription factor regulating oxidative metabolism in the SGA group. We further show that E2F1 regulates the differential transcriptome found in SGA derived MSCs and is associated with the activating histone marks H3K27ac and H3K4me3. One of the key genes regulated by E2F1 was found to be the fatty acid elongase ELOVL2, a gene involved in the endogenous synthesis of docosahexaenoic acid (DHA). Finally, we shed light on how the E2F1-ELOVL2 pathway may alter oxidative respiration in the SGA condition by contributing to the maintenance of cellular metabolic homeostasis.
Highlights
There is a developmental component to the origin of metabolic diseases such as obesity, type 2 diabetes mellitus, and cardiovascular disease
Our results show that small for gestational age (SGA)-derived Mesenchymal Stem Cells (MSCs) generally have a significantly lower oxygen consumption rate (OCR) readout compared to their appropriate for gestational age (AGA) counterparts (Fig 1A), indicative of differences in energy metabolism
We discovered ELOVL2 as a gene regulated by E2F1 in the context of fetal growth restriction
Summary
There is a developmental component to the origin of metabolic diseases such as obesity, type 2 diabetes mellitus, and cardiovascular disease. Studies focused on fetal growth impairment as a risk factor for later disease [1, 2]. Whereas suboptimal prenatal nutrient supply and placental dysfunction can impair fetal growth, the long-term effects of early experience that increase an individual’s metabolic risk are thought to be dependent on altered epigenetic regulation of gene expression established within a critical window of fetal development [3,4,5]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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