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Influence of Prenatal Transportation Stress-Induced Differential DNA Methylation on the Physiological Control of Behavior and St

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Influence of Prenatal Transportation Stress-Induced Differential DNA Methylation on the Physiological Control of Behavior and St Copyedited by: KD Journal of Animal Science, 2020, 1–18 doi:10.1093/jas/skz368 Advance Access publication December 6, 2019 Received: 31 August 2019 and Accepted: 5 December 2019 Fetal Programming Downloaded from https://academic.oup.com/jas/article-abstract/98/1/skz368/5661111 by Texas A&M College Station user on 30 April 2020 Fetal Programming Influence of prenatal transportation stress-induced differential DNA methylation on the physiological control of behavior and stress response in suckling Brahman bull calves Brittni P. Littlejohn,†,‡,1 Deborah M. Price,†,‡ Don A. Neuendorff,† Jeffery A. Carroll,|| Rhonda C. Vann,$ Penny K. Riggs,‡ David G. Riley,‡ Charles R. Long,†,‡ Ronald D. Randel,† and Thomas H. Welsh, Jr.‡,2 †Texas A&M AgriLife Research & Extension Center, Overton, TX 75684, ‡Department of Animal Science, Texas A&M University, and Texas A&M AgriLife Research, College Station, TX 77843, ||USDA-ARS, Livestock Issues Research Unit, Lubbock, TX 79403, $Mississippi Agricultural and Forestry Experiment Station, Mississippi State University, Raymond, MS 39154 1Current address: Department of Animal and Dairy Sciences, Mississippi State University, Mississippi State, MS 39762 2Corresponding author: [email protected] Abstract The objective of this experiment was to examine potential differential methylation of DNA as a mechanism for altered behavioral and stress responses in prenatally stressed (PNS) compared with nonprenatally stressed (Control) young bull calves. Mature Brahman cows (n = 48) were transported for 2-h periods at 60 ± 5, 80 ± 5, 100 ± 5, 120 ± 5, and 140 ± 5 d of gestation (Transported group) or maintained as nontransported Controls (n = 48). From the offspring born to Transported and Control cows, a subset of 28-d-old intact bulls (n = 7 PNS; n = 7 Control) were evaluated for methylation of DNA of behavior and stress response–associated genes. Methylation of DNA from white blood cells was assessed via reduced representation bisulfite sequencing methods. Because increased methylation of DNA within gene promoter regions has been associated with decreased transcriptional activity of the corresponding gene, differentially methylated (P ≤ 0.05) CG sites (cytosine followed by a guanine nucleotide) located within promoter regions (n = 1,205) were used to predict (using Ingenuity Pathway Analysis software) alterations to canonical pathways in PNS compared with Control bull calves. Among differentially methylated genes (P ≤ 0.05) related to behavior and the stress response were OPRK1, OPRM1, PENK, POMC, NR3C2, TH, DRD1, DRD5, COMT, HTR6, HTR5A, GABRA4, GABRQ, and GAD2. Among altered (P < 0.05) signaling pathways related to behavior and the stress response were Opioid Signaling, Corticotropin-Releasing Hormone Signaling, Dopamine Receptor Signaling, Dopamine-DARPP32 Feedback in cAMP Signaling, Serotonin Receptor Signaling, and GABA Receptor Signaling. Alterations to behavior and stress response–related genes and canonical pathways supported previously observed elevations in temperament score and serum cortisol through weaning in the larger population of PNS calves from which bulls in this study were derived. Differential methylation of DNA and predicted alterations to behavior and stress response–related pathways in PNS compared with Control bull calves suggest epigenetic programming of behavior and the stress response in utero. Key words: behavior, bovine, epigenetics, prenatal stress, stress response, temperament © The Author(s) 2019. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: [email protected]. 1 Copyedited by: KD 2 | Journal of Animal Science, 2020, Vol. 98, No. 1 Introduction Animal Procedures Alteration of behavior and stress responsiveness is among the Mature Brahman cows were assigned to 1 of 2 treatment most noted outcomes of prenatal stress (PNS) in mammals groups (Transported: n = 48 and Control: n = 48), which were (Lindsay et al., 2019; Matthews and McGowan, 2019). The balanced by age, parity, and temperament (Littlejohn et al., mechanisms controlling these alterations are still largely 2016). Transported cows were hauled for 2 h at 60 ± 5, 80 ± 5, unclear; however, it is known that stress incurred by a gestating 100 ± 5, 120 ± 5, and 140 ± 5 d of gestation (Price et al., 2015). dam can result in suppression of the placental barrier enzyme Control cows were managed the same as Transported cows 11β-hydroxysteroid dehydrogenase type 2 (11-βHSD2). This with the exception of being transported. Both treatment groups Downloaded from https://academic.oup.com/jas/article-abstract/98/1/skz368/5661111 by Texas A&M College Station user on 30 April 2020 enzyme converts cortisol to an inactive form prior to entering were housed in the same pasture (at the Texas A&M AgriLife fetal circulation; therefore, decreased 11-βHSD2 can result Research and Extension Center at Overton, TX) and fed the in increased fetal exposure to corticosteroids (Benediktsson same diet (Littlejohn et al., 2016). From these groups, 26 male et al., 1997; Stirrat et al., 2018). Such alterations to the fetal and 18 female calves (Control group) were born to Control dams, environment may result in epigenetic modifications, such whereas 20 male and 21 female calves (Prenatally Stressed, as DNA methylation, which appear to be major regulators of PNS, group) were born to Transported dams. Male calves phenotypic changes due to prenatal stress (Szyf, 2012; Lester were maintained as bulls throughout the study. Each calf was and Marist, 2018). Deoxyribonucleic acid methylation is defined manually restrained for less than 5 min for sample collection as a covalent modification in which a methyl group is added at 28 d of age. One 10-mL vacuum tube (BD, Franklin Lakes, NJ) to the carbon 5 position of a cytosine nucleotide (Wyatt, 1950; containing EDTA was used to collect the blood sample from each Razin and Riggs, 1980). Increased methylation of DNA within calf via jugular venipuncture with a sterile 18-gauge needle. the promoter region of a gene has been reported to suppress Leukocytes were isolated and stored at −80 °C until DNA was transcriptional activity and gene expression (Levine et al., 1991; extracted. Samples from bull calves were stratified into groups Tate and Bird, 1993), whereas increased methylation of DNA in based on the following criteria: 1) adequate availability of DNA, the gene body region of a gene has been suggested to result in 2) calf treatment group, and 3) calf sire. From those stratified increased gene expression (Hellman and Chess, 2007). Therefore, groups, DNA samples from 7 PNS and 7 Control bull calves were the presence or absence of methyl groups at specific locations randomly selected for analysis in this study. within a gene can be utilized as a tool to better understand how prenatal environment shaped postnatal phenotype. Behavior Sample Analysis and stress response traits are multifaceted in nature and Processing of blood samples controlled by many components of neural, neuroendocrine, and Blood samples were centrifuged at 2,671 × g for 30 min at 6 °C. endocrine systems (Chan et al., 2018; Bale et al., 2019). Some Leukocytes were isolated and transferred into 2-mL nuclease- of these systems include the hypothalamic–pituitary–adrenal free microcentrifuge tubes. Samples were washed in red blood (HPA) axis and signaling by catecholamines, monoamines, and cell lysis buffer solution repeatedly until a clean cell pellet was opioids. Differential transcript abundance in the adrenal cortex produced. Leukocyte samples were stored at −80 °C until they (Friedrich et al., 2017) and differential methylation of DNA in were thawed for DNA isolation procedures. different brain regions (Cantrell et al., 2019) have been associated with temperament in cattle. Furthermore, emerging literature DNA extraction supports the ability of glucocorticoids to alter methylation of Phenol-chloroform extraction procedures were used to isolate DNA in developing neural cells; specifically, in vitro exposure DNA from each leukocyte pellet for DNA methylation analysis of early neural progenitor cells to dexamethasone resulted in by standard procedures as previously described (Littlejohn et al., genome-wide differences in methylation of DNA (Provençal 2018). Following DNA precipitation, purified DNA was stored at et al., 2019). Because behavior and stress response phenotypes −80 °C and submitted to Zymo Research Corp (Irvine, CA) for are of economic and biologic significance to beef cattle DNA methylation analysis. production, this study sought to understand the mechanisms by which a common stressor for beef cattle, transportation, Library construction for DNA methylation analysis incurred by a pregnant dam could affect behavior and the stress A method of reduced representation bisulfite sequencing, response of offspring. The objective of this study was to identify Methyl-MiniSeq (Zymo Research; Irvine, CA), was utilized to differentially methylated genes from a previously reported evaluate differential methylation of DNA in samples from PNS genome-wide assessment of DNA methylation in prenatally compared with Control bull calves. Libraries were prepared from stressed bull calves that were related to behavior and stress 200 to 500 ng of genomic DNA digested with 60 units of TaqαI responses (Littlejohn et al., 2018). Because behavior and stress and 30 units of MspI (New England Biolabs, Inc., Ipswich, MA) response phenotypes were altered in the
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  • Supplemental Figures 04 12 2017
    Jung et al. 1 SUPPLEMENTAL FIGURES 2 3 Supplemental Figure 1. Clinical relevance of natural product methyltransferases (NPMTs) in brain disorders. (A) 4 Table summarizing characteristics of 11 NPMTs using data derived from the TCGA GBM and Rembrandt datasets for 5 relative expression levels and survival. In addition, published studies of the 11 NPMTs are summarized. (B) The 1 Jung et al. 6 expression levels of 10 NPMTs in glioblastoma versus non‐tumor brain are displayed in a heatmap, ranked by 7 significance and expression levels. *, p<0.05; **, p<0.01; ***, p<0.001. 8 2 Jung et al. 9 10 Supplemental Figure 2. Anatomical distribution of methyltransferase and metabolic signatures within 11 glioblastomas. The Ivy GAP dataset was downloaded and interrogated by histological structure for NNMT, NAMPT, 12 DNMT mRNA expression and selected gene expression signatures. The results are displayed on a heatmap. The 13 sample size of each histological region as indicated on the figure. 14 3 Jung et al. 15 16 Supplemental Figure 3. Altered expression of nicotinamide and nicotinate metabolism‐related enzymes in 17 glioblastoma. (A) Heatmap (fold change of expression) of whole 25 enzymes in the KEGG nicotinate and 18 nicotinamide metabolism gene set were analyzed in indicated glioblastoma expression datasets with Oncomine. 4 Jung et al. 19 Color bar intensity indicates percentile of fold change in glioblastoma relative to normal brain. (B) Nicotinamide and 20 nicotinate and methionine salvage pathways are displayed with the relative expression levels in glioblastoma 21 specimens in the TCGA GBM dataset indicated. 22 5 Jung et al. 23 24 Supplementary Figure 4.
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