Rumen protected methyl donors and the genome beyond nutrigenomics
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Rumen protected methyl donors and the genome beyond nutrigenomics
- 1. Rumen-protected methyl donors and the genome: beyond nutrigenomics Juan J. Loor, Zheng Zhou, and Mario Vailati-Riboni Department of Animal Sciences, Division of Nutritional Sciences, and Illinois Informatics Institute University of Illinois, Urbana-Champaign, USA XXI ASPA Congress June 9‐12, 2015 Milan, Italy
- 2. Outline • Brief “history” • Nutritional and physiological context • Nutrigenomics Met and choline • Beyond nutrigenomics Can we “prime” cow and calf??
- 5. Substrate = e.g. CpG site SAM = S‐adenosylmethionine DNMT = DNA methyl transferase Methyl donor cycle regulation: non‐ruminants MAT1A + + ‐ ATP MAT1A control: Genome level Promoter methylation (Huh‐7 cells) (Tomasi et al., 2012) Certain microRNA ↓ mRNA (Yang et al., 2012) Enzyme level Feed‐forward activation by Met (sheep) (Xue and Snoswell, 1989) Feed‐back inhibition by SAM (sheep) (Xue and Snoswell, 1989) (e.g. GNMT, DNMT) ROM ‐ ↑ Metabolism ↑ Oxidative stress BHMT+MTR + Glutathione+ Oxidase
- 6. Methyl donor requirements differ during the life stages of ruminants (Pinoti et al., 2002) Adult ruminant greater requirements due to ruminal degradation of dietary sources Use of “rumen‐protection” technology important (MTR) (MTR)
- 7. History of rumen‐protection: amino acids and choline Journal of Dairy Science papers: 1968 ‐ First paper in JDS: Griel, Patton, McCarthy and Chandler “Milk production response to feeding methionine‐hydroxy analog (MHA) to lactating cows” 1970: Broderick, Kowalzyk and Satter “Milk production response to supplementation with encapsulated methionine per os or casein per abomasum” (Delmar Chemical, Ontario) 2006: Rulquin et al. “Effect of different forms of methionine on lactation performance of dairy cows” 2007: Cooke et al. “Supplemental choline for prevention and alleviation of fatty liver in dairy cattle” 2011: Chen et al. “Effect of feeding different sources of rumen protected methionine on milk production and N utilization in lactating dairy cows” 2011: Zom et al. “Effect of rumen‐protected choline on performance, blood metabolites, and hepatic triacylglycerols of periparturient dairy cattle” Also, Noftsger and St‐Pierre (2003), Noftsger et al. (2005), Socha et al. (2005), St‐Pierre and Sylvester (2005), Ordway et al. (2009), Appuhamy et al. (2011), Lee et al. (2012), Osorio et al. (2013), Osorio et al. (2014ab)
- 8. Dietary methyl‐donors in dairy cows SAM SAH Homocysteine Cysteine Diet Tissues Milk Liver health DNA methylation Epigenetics VLDLPC Vit. B12 CH3 PE rRNA complex Protein synthesis initiation Choline Betaine Dimethylglycine Diet 5-MTHF Methionine Diet Folate + + + Cooke et al. 2007 Zom et al. 2011 + Glutathione Antioxidants Taurine + Embryo Fetus
- 9. Pre‐calving Post‐calving ~3‐4 wk ~3‐4 wkCalving (Block et al., 2001) Energy balance Body condition score Energy intake 4% Fat corrected milk (Ingvartsen, 2006) Transition period Tissue mobilization
- 11. (Bertoni and Trevisi, 2013) Inflammation and oxidative stress occur during transition • Acidosis • Metritis • Retained placenta • High NEFA and BHBA (++)
- 13. DMI (kg/d) Day relative to calving Day relative to calving Diet P = 0.67 Time P <.001 DxT P = 0.42 Diet P = 0.18 Time P <.001 DxT P = 0.78 Met P = 0.06 Control MetaSmart Smartamine Met = Control vs MetaSmart + Smartamine ~7 g Met/d supplemented ~10 g Met/d supplemented
- 14. Better performance with Methionine Parameter Diet SE P‐value Control MetaSmart Smartamine Diet Met Par Time D×T Milk yield (kg/d) 35.7 38.1 40.0 1.6 0.15 0.08 ‐‐ <0.01 0.86 Milk fat (%) 4.27 4.68 4.09 0.22 0.59 0.36 .05 <0.01 0.01 Milk protein (%) 3.04 3.26 3.19 0.08 0.13 0.05 ‐‐ <0.01 0.23 Milk fat yield (kg/d) 1.64 1.84 1.81 0.08 0.11 0.04 ‐‐ 0.04 0.01 Milk protein Yield (kg/d) 1.11 1.23 1.24 0.05 0.08 0.03 ‐‐ 0.02 0.14 ECM (kg/d) 41.0 44.8 45.0 1.55 0.09 0.03 ‐‐ <0.01 0.07 Milk yield and components Met = Control vs MetaSmart + Smartamine (Osorio et al., 2013)
- 15. Day after parturition 0 5 10 15 20 25 30 35 kg/d 10 12 14 16 18 20 22 24 26 Control Methionine Choline Recent experiment confirms the benefit of rumen‐protected Methionine • Dry matter intake during last 3 wk prepartum greater (1‐2 kg/d) with Methionine • Milk protein % greater with Methionine • Lower inflammatory and oxidative stress status Day aftyer parturition 0 5 10 15 20 25 30 35 kg/d 20 25 30 35 40 45 50 55 Control Methionine Choline Dry matter intakeMilk productionMet P = 0.03 Chol P = 0.41 Day P < 0.01 Met P = 0.02 Chol P = 0.90 Day P < 0.01 (Zhou et al., 2015 Abs. 455, JAM Orlando, FL, USA)
- 19. -10.0 7.0 21.0 -10.0 7.0 21.0 -10.0 7.0 21.0 CO MS SM 1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 2 3 4 5 -10.0 7.0 21.0 -10.0 7.0 21.0 -10.0 7.0 21.0 CO MS SM 1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 2 3 4 5 Smartamine + Control MetaSmart + Control Control (higher-energy, “close-up” to calving) Rumen-protected Methionine alters the liver transcriptome 2,663 genes with diet time effect (Osorio et al., 2013)
- 20. The 12 most-impacted metabolic pathways with rumen-protected Methionine Impact 0 200 400 600 800 1000 1200 1400 1600 Cyanoamino acid metabolism Taurine and hypotaurine metabolism Lipoic acid metabolism Propanoate metabolism Pyruvate metabolism Cysteine and methionine metabolism Glyoxylate and dicarboxylate metabolism Riboflavin metabolism Valine, leucine and isoleucine biosynthesis Glutathione metabolism Glycolysis and gluconeogenesis Citrate cycle (TCA cycle) Carbohydrate metabolism Antioxidants **These are key pathways responsible for the adaptations in liver to parturition and rumen‐protected Methionine supplementation
- 22. Transcription regulator Function Frequency FBJ osteosarcoma oncogene (FOS) Regulates cell proliferation, differentiation, and transformation Associated with apoptosis 7 of 18 Ets homologous factor (EHF) Repressor of cellular differentiation 6 of 18 Kruppel‐like factor 4 (KLF4) Repressor of cellular proliferation Promotes cell survival 6 of 18 Kruppel‐like factor 5 (KLF4) Transcriptional activator Promotes and suppresses cell proliferation and cell growth 6 of 18 v‐myc avian myelocytomatosis viral oncogene homolog (MYC) Regulates cell cycle progression, apoptosis, and cellular transformation 6 of 18 Top 5 most-frequently affected transcription regulators with rumen-protected Methionine (Zhou et al., in review)
- 23. At day 7 postpartum EHF down-regulated 2.4-fold in cows fed Methionine vs. control Biological meaning of transcription regulator networks? At day 7 vs. -10 d postpartum EHF down-regulated 1.7-fold in cows fed Methionine • Methionine could have direct anti- inflammatory role through EHF
- 25. Bioinformatics analysis revealed unique biological responses to rumen‐protected Met Immune func on ↓ Nutrient metabolism ↑ Endocrine signaling ↓ • Functional outcome still unknown • Epigenomic alterations??
- 26. Methionine and mTOR signalling Met? Potential mechanisms: • Binding directly to regulatory site on mTOR • Binding to a co- regulator of mTOR (indirect) • Stimulating a protein kinase
- 30. Methylation status mRNA expression • These were newborn piglets • Functional outcome on gluconeogenic flux was small • Longer-term study needed e.g. through weaning transition
- 31. • Findings indicate a physiological benefit of supplementing rumen‐protected Met during the transition period • Underscore the importance of maintaining an adequate Met:Lys balance • Clear nutrigenomics effects • Likely epigenomic effects Met : Lys Conclusions
- 34. Acknowledgements