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Maternal Folic Acid Supplementation and Its Effects on Metabolic and Epigenetic Regulatory Gene Networks in Offspring

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Maternal Folic Acid Supplementation and Its Effects on Metabolic and Epigenetic Regulatory Gene Networks in Offspring Maternal Folic Acid Supplementation and Its Effects on Metabolic and Epigenetic Regulatory Gene Networks in Offspring Wing Hong Chu Discipline of Obstetrics and Gynaecology School of Medicine Faculty of Health Sciences University of Adelaide South Australia Australia A thesis submitted in fulfilment of the degree of Doctor of Philosophy (PhD) July 2018 ii “All that we see or seem is but a dream within a dream.” – Edgar Allan Poe iii iv Dedicated to Mum, Dad and Wing Ho v vi Table of contents TABLE OF CONTENTS .......................................................................................VII ABSTRACT ..........................................................................................................XII DECLARATION .................................................................................................. XVI ACKNOWLEDGEMENTS ................................................................................. XVII ABSTRACTS ARISING FROM THIS THESIS ................................................... XIX LIST OF FIGURES ............................................................................................. XXI LIST OF TABLES ............................................................................................. XXIII ABBREVIATIONS ............................................................................................ XXVI CHAPTER 1............................................................................................................ 1 1.1. INTRODUCTION ...................................................................................... 2 1.1.1. FOLATE ABSORPTION AND TRANSPORT ......................................... 3 1.1.2. FOLATE IN ONE-CARBON METABOLISM ........................................... 7 1.1.3. MATERNAL ONE-CARBON METABOLISM AND THE ESTABLISHMENT OF FOETAL METHYLATION PATTERNS ...................... 10 1.1.4. FOLATE AND DNA METHYLATION .................................................... 11 1.1.5. DNA METHYLATION AND THE REGULATION OF GENE EXPRESSION ............................................................................................... 12 1.1.6. PHYSIOLOGICAL REQUIREMENTS OF FOLATE DURING PERICONCEPTION, PREGNANCY AND LACTATION ................................ 14 1.1.7. PERICONCEPTIONAL FOLIC ACID SUPPLEMENTATION AND PREGNANCY OUTCOMES IN HUMANS ..................................................... 16 1.1.8. MATERNAL FOLIC ACID SUPPLEMENTATION AND PREGNANCY OUTCOMES IN HUMANS ............................................................................. 21 1.1.9. FOLATE AND MATERNAL PHYSIOLOGY AND METABOLISM ......... 21 1.1.10. FOLATE IN EMBRYONIC AND FOETAL DEVELOPMENT IN NON- HUMAN STUDIES ......................................................................................... 22 1.1.11. FOLATE AND EPIGENETIC REGULATION: HUMAN STUDIES .... 23 vii 1.1.12. FOLATE AND DEVELOPMENTAL PROGRAMMING: HUMAN STUDIES ....................................................................................................... 24 1.1.13. FOLATE AND DEVELOPMENTAL PROGRAMMING: NON-HUMAN STUDIES ....................................................................................................... 25 1.1.14. MICRORNAS ................................................................................... 27 1.1.15. MICRORNA BIOGENESIS .............................................................. 27 1.1.16. MATERNAL ADAPTATIONS DURING PREGNANCY AND THE ROLE OF MICRORNAS ................................................................................ 36 1.1.17. FOETAL DEVELOPMENT AND THE ROLE OF MICRORNAS: NON- HUMAN SPECIES ......................................................................................... 38 1.1.18. MICRORNAS IN METABOLIC REGULATION ................................ 42 1.1.19. SUMMARY AND GENERAL CONCLUSION ................................... 46 1.2. GENERAL HYPOTHESES ..................................................................... 49 1.2.1. SPECIFIC HYPOTHESES ................................................................... 49 1.3. AIMS ....................................................................................................... 50 CHAPTER 2 .......................................................................................................... 51 2.1. INTRODUCTION .................................................................................... 52 2.2. METHODS .................................................................................................. 55 2.2.1. ANIMALS AND TISSUE COLLECTION ............................................... 55 2.2.2. RNA EXTRACTION AND QUALITY ANALYSIS .................................. 56 2.2.3. AFFYMETRIX GENECHIP® RAT GENE 1.0 ST ARRAY PREPARATION ............................................................................................. 56 2.2.4. AFFYMETRIX MICROARRAY DATA NORMALISATION AND ANALYSIS ..................................................................................................... 57 2.2.5. QUANTIFICATION OF MRNA EXPRESSION ..................................... 58 2.2.6. DATA PROCESSING AND STATISTICAL ANALYSIS FOR MRNA EXPRESSION ............................................................................................... 59 2.2.7. BIOINFORMATICS ANALYSIS ............................................................ 59 2.2.8. INGENUITY PATHWAY ANALYSIS .................................................... 60 2.3. RESULTS ............................................................................................... 61 2.3.1. EFFECTS OF MATERNAL FOLIC ACID SUPPLEMENTATION ON GLOBAL TRANSCRIPTOMIC CHANGES IN THE LIVER OF ADULT OFFSPRING .................................................................................................. 61 viii 2.3.2. HIERARCHICAL CLUSTERING AND INGENUITY PATHWAY ANALYSIS FOR THE DIFFERENTIALLY EXPRESSED GENES IN ADULT OFFSPRING .................................................................................................. 71 2.3.3. HIERARCHICAL CLUSTERING AND INGENUITY PATHWAY ANALYSIS FOR THE DIFFERENTIALLY EXPRESSED GENES IN ADULT MALE OFFSPRING ....................................................................................... 74 2.3.4. HIERARCHICAL CLUSTERING AND INGENUITY PATHWAY ANALYSIS FOR THE DIFFERENTIALLY EXPRESSED GENES IN ADULT FEMALE OFFSPRING................................................................................... 77 2.3.5. BIOINFORMATICS ANALYSIS ............................................................ 83 2.3.6. INDEPENDENT QUANTIFICATION OF MRNA EXPRESSION IN LIVER OF ADULT OFFSPRING .................................................................... 84 2.4. DISCUSSION ......................................................................................... 90 CHAPTER 3.......................................................................................................... 95 3.1. INTRODUCTION .................................................................................... 96 3.2. METHODS ............................................................................................ 100 3.2.1. ANIMALS AND TISSUE COLLECTION ............................................. 100 3.2.2. RNA EXTRACTION AND QUALITY ANALYSIS ................................ 101 3.2.3. QUANTIFICATION OF MRNA EXPRESSION ................................... 101 3.2.4. DATA PROCESSING AND STATISTICAL ANALYSIS FOR MRNA EXPRESSION ............................................................................................. 102 3.2.5. EXIQON MICRORNA MICROARRAY ANALYSIS ............................. 103 3.2.6. QUANTIFICATION OF SELECTED MICRORNA EXPRESSION ...... 104 3.2.7. DATA PROCESSING AND STATISTICAL ANALYSIS FOR MICRORNA EXPRESSION ......................................................................... 105 3.2.8. MICRORNA BIOINFORMATICS AND TARGET PREDICTION ANALYSES .................................................................................................. 106 3.2.9. INGENUITY PATHWAY ANALYSIS .................................................. 106 3.3. RESULTS ............................................................................................. 108 3.3.1. EFFECTS OF MATERNAL FOLIC ACID SUPPLEMENTATION ON MATERNAL AND FOETAL MORPHOMETRY ............................................ 108 ix 3.3.2. EFFECTS OF MATERNAL FOLIC ACID SUPPLEMENTATION ON GLOBAL MATERNAL AND FOETAL HEPATIC MICRORNA EXPRESSION ... ....................................................................................................... 111 3.3.3. GENOMICS OF DIFFERENTIALLY EXPRESSED MATERNAL AND FOETAL HEPATIC MICRORNAS................................................................ 112 3.3.4. PREDICTED AND VALIDATED TARGETS OF THE DIFFERENTIALLY EXPRESSED MICRORNAS IN FOETUSES AND DAMS ........................... 113 3.3.5. INGENUITY PATHWAY ANALYSIS FOR THE DIFFERENTIALLY EXPRESSED HEPATIC MICRORNAS IN ALL FOETUSES ....................... 115 3.3.6. INGENUITY PATHWAY ANALYSIS FOR THE DIFFERENTIALLY EXPRESSED HEPATIC MICRORNAS IN FEMALE FOETUSES ............... 115 3.3.7. INGENUITY PATHWAY ANALYSIS FOR THE DIFFERENTIALLY EXPRESSED HEPATIC MICRORNAS IN DAMS ........................................ 116 3.3.8. QUANTIFICATION OF MATERNAL AND FOETAL HEPATIC MICRORNA EXPRESSION ......................................................................... 119 3.3.9. EFFECTS OF MATERNAL FOLIC ACID SUPPLEMENTATION ON MATERNAL AND FOETAL HEPATIC EXPRESSION OF METABOLIC REGULATORY GENES ..............................................................................
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