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Transcriptomic profiling of cerebrum, liver, and muscle tissues of 50 days fetuses in response to early maternal nutrient restriction

ABSTRACT: We addressed the molecular mechanisms and biological processes underlying the differences in cerebrum, liver, and muscle gene expression of 50 days fetuses in response to early maternal nutrient restriction. To this end, we employed tissue-to-tissue and tissue-specific network approaches using the genome-wide expression profile of 14 samples for two experimental conditions [Control – CON (n = 7) and 40% nutrient restriction – RES (n = 7)]. After RNA quality control, read mapping was performed with STAR aligner to the bovine ARS-UCD1.2 reference genome. Count normalization was performed by using the VST function from DESEq2. Gene networks were constructed using the PCIT algorithm, whereas differentially co-expressed genes were identified based on the R-package DGCA. Significant gene-gene co-expression was taken based on r > | 0.9| and then filtered by differentially expressed genes and transcription factors. Networks were visualized in Cytoscape, and functional analyses were carried out on Cluego and ShinyGo tools. We found that the cerebrum, liver, and muscle tissues were affected by nutrient restriction leading to differences in transcriptional regulation between CON and RES groups. Furthermore, we shed light on the nutrient-sensing pathways across tissues such as mTOR, PI3K/Akt, and insulin. This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2016-67016-24946 from the USDA National Institute of Food and Agriculture as well as the USDA-NIFA-AFRI (2018-67011-31708).

ORGANISM(S): Bos taurus

PROVIDER: GSE154299 | GEO | 2021/02/08

REPOSITORIES: GEO

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Project description:The objective was to evaluate the effect of nutrient restriction and intramammary lipopolysaccharide (LPS) challenge on mammary gland (MG) gene expression in early lactation cows. At 24 ± 3 d in milk, multiparous cows were either allowed to continue ad libitum intake of a lactation diet (CON, n = 6), or the ration was diluted with barley straw (48% DM) for 4 d (RES, n = 6). On d 3, one healthy rear mammary quarter was infused with 50 µg of LPS. Mammary biopsies were performed 24 h after LPS challenge. RNA and proteins analyzed using bovine 44K microarrays (Agilent Technologies) and micro-LC-MS/MS, respectively. Transcriptomic data were analyzed using GeneSpring (moderated-t-test with Westfall-Young correction, P < 0.05). Proteins were analyzed with Progenesis LC-MS software v4.1 (Nonlinear Dynamics). Production and energy balance did not differ prior to diet change. Negative energy balance was aggravated in RES (41 vs 97 ± 15 % of requirements, mean ± SD; P < 0.001). A total of 87 differentially expressed genes (DEG) were highlighted through the comparison of RES vs CON group. Among the 33 DEG identified in the transcriptomic analyses, 11 and 22 were down- and upregulated by restriction, respectively. Among the upregulated DEG, there were PDK4 and CPT1A which are involved in the regulation of fatty acid, ketone, and glucose metabolism. CPT1A is the key enzyme in the carnitine dependent fatty acid transport, promoting fatty acid oxidation. Genes involved in immune response such as PGLYRP3 and TRIB2 were upregulated, suggesting a higher inflammatory response in RES than CON. Proteomic analysis identified 54 proteins with 14 up- and 40 downregulated in RES cows. Upregulated proteins were mostly involved in gene expression mechanisms such as translation, RNA splicing and cellular protein modification. The downregulated proteins (e.g., EIF3H, RS27A, RS15) take part in protein metabolism. This is coherent with transcriptomic results, namely the downregulation of RPL 37A, a component of ribosomal complex, which catalyzes protein synthesis and may partially explain the lower milk protein yield in RES (834 vs 1163 g/d; P = 0.02). Proteins involved in antigen processing and presentation were downregulated in RES compared to CON, suggesting an impaired ability to counteract inflammation in RES MG. Preliminary transcriptomics and proteomics analyses show that undernutrition may influence the MG response to inflammation at each level of gene expression.

Project description:Aside from the perinatal complications associated with low birth weight, individuals born with intra-uterine growth restriction suffer from chronic diseases late in life that ultimately lead to a shortened lifespan. These late life metabolic sequelae of low birth weight include obesity and metabolic syndrome, diabetes mellitus, cardiovascular disease, hypertension, stroke, dyslipidemia, and non-alcoholic fatty liver disease/steatohepatitis. Animal models employing perinatal calorie restriction recapitulate the observations made in humans. Interestingly, if continued calorie restriction is employed post-natally the late life sequelae of intra-uterine growth restriction are ameliorated. These observations linking both fetal and early post natal growth to later health is now termed the developmental origins of health and disease. To further our understanding of the mechanism of how early growth affects late life health we have employed Affymetrix microarray-based expression profiling to characterize hepatic gene expression in a rat model of maternal semi-nutrient restriction. In these experiments we have limited maternal calorie intake to 50% of normal so as to create 3 groups of animals: Control (Con) male offspring born to mothers who were fed normally throughout gestation and lactation; intra-uterine calorie restricted male offspring (IUCR) born to mothers who had 50% restriction of calories from e11 to e21; and combined intra-uterine and post-natal calorie restriction (IPCR) male offspring who were born to mothers who received calorie restriction during both fetal growth (e11 to e21) and post-natally (p1-p21). Livers were collected at p21(day 21 of life) for Con and IPCR groups (IUCR withheld owing to ‘catch up” growth), and at p450 (day 450 of life) for Con, IUCR, and IPCR. The profiling data reveals clear alteration of circadian cycling at P21, and subtle changes for circadian gene expression at p450. In addition, a clear transcriptional response is found during active calorie restriction at p21 but an absence of a transcriptional response late in life at p450. Transcritional studies have been performed using Affymetrix Rat Gene 1.0 arrays for the following treatment groups, with each group run in triplicate (each replicate from separate littermates): Day 21 Control, Day 21 IPCR, Day 450 Con, Day 450 IUCR, Day 450 IPCR

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Transcriptomic profiling of cerebrum, liver, and muscle tissues of 50 days fetuses in response to early maternal nutrient restriction

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