Epigenetic modifications: basic mechanisms and role in cardiovascular disease.

The term epigenetics was first used to refer to the complex interactions between the genome and the environment that are involved in development and differentiation in higher organisms. Today, this term is used to refer to heritable alterations that are not due to changes in DNA sequence. Rather, epigenetic modifications, or tags, such as DNA methylation and histone modification, alter DNA accessibility and chromatin structure, thereby regulating patterns of gene expression. These processes are crucial to normal development and differentiation of distinct cell lineages in the adult organism. They can be modified by exogenous influences, and as such, they can contribute to or be the result of environmental alterations of phenotype or pathophenotype. Importantly, epigenetic programming has a crucial role in the regulation of pluripotency genes, which become inactivated during differentiation. Here, we review the major mechanisms in epigenetic regulation; highlight the role of stable, long-term epigenetic modifications that involve DNA methylation; and discuss those modifications that are more flexible (short-term) and involve histone modifications, such as methylation and acetylation. We will also discuss the role of nutritional and environmental challenges in generational inheritance and epigenetic modifications, concentrating on examples that relate to complex cardiovascular diseases, and specifically dissect the mechanisms by which homocysteine modifies epigenetic tags. Lastly, we will discuss the possibilities of modifying therapeutically acquired epigenetic tags, summarizing currently available agents and speculating on future directions. Chromatin is the complex of chromosomal DNA associated with proteins in the nucleus (for review, see Campos and Reinberg1). DNA in chromatin is packaged around histone proteins, in units referred to as nucleosomes. A nucleosome has 147 base pairs of DNA associated with an octomeric core of histone proteins, which consists of 2 H3-H4 histone dimers surrounded by 2 H2A-H2B dimers. N-terminal histone tails protrude from nucleosomes into the nuclear lumen. …

[1]  Shih-Ann Chen,et al.  Histone deacetylase inhibition improved cardiac functions with direct antifibrotic activity in heart failure. , 2013, International journal of cardiology.

[2]  J. Loscalzo,et al.  Hypoxia: a master regulator of microRNA biogenesis and activity. , 2013, Free radical biology & medicine.

[3]  René F. Ketting,et al.  PIWI-interacting RNAs: from generation to transgenerational epigenetics , 2013, Nature Reviews Genetics.

[4]  Gene Kim,et al.  The role of redox signaling in epigenetics and cardiovascular disease. , 2013, Antioxidants & redox signaling.

[5]  J. Backs,et al.  HDAC4 controls histone methylation in response to elevated cardiac load. , 2013, The Journal of clinical investigation.

[6]  Toshiyuki Yamamoto,et al.  CONFLICT OF INTEREST: None declared. , 2013 .

[7]  B. Dahal,et al.  Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. , 2012, American journal of respiratory and critical care medicine.

[8]  J. Mattick,et al.  Long Noncoding RNAs in Cardiac Development and Pathophysiology , 2012, Circulation research.

[9]  E. Olson,et al.  A Role for miR-145 in Pulmonary Arterial Hypertension: Evidence From Mouse Models and Patient Samples , 2012, Circulation research.

[10]  J. Loscalzo,et al.  Holding our breath: The emerging and anticipated roles of microRNA in pulmonary hypertension , 2012, Pulmonary circulation.

[11]  T. McKinsey,et al.  Histone Deacetylation Inhibition in Pulmonary Hypertension: Therapeutic Potential of Valproic Acid and Suberoylanilide Hydroxamic Acid , 2012, Circulation.

[12]  Q. T. Wang.  Epigenetic regulation of cardiac development and function by polycomb group and trithorax group proteins , 2012, Developmental dynamics : an official publication of the American Association of Anatomists.

[13]  Y. Shi,et al.  Tet family proteins and 5-hydroxymethylcytosine in development and disease , 2012, Development.

[14]  Andrea Soricelli,et al.  Contemporary Reviews in Cardiovascular Medicine Primary Prevention of Atherosclerosis A Clinical Challenge for the Reversal of Epigenetic Mechanisms , 2012 .

[15]  Albert-László Barabási,et al.  MicroRNA-21 Integrates Pathogenic Signaling to Control Pulmonary Hypertension: Results of a Network Bioinformatics Approach , 2012, Circulation.

[16]  T. McKinsey,et al.  Selective Class I Histone Deacetylase Inhibition Suppresses Hypoxia-Induced Cardiopulmonary Remodeling Through an Antiproliferative Mechanism , 2012, Circulation research.

[17]  G. Owens,et al.  Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. , 2012, Annual review of physiology.

[18]  Cuk-Seong Kim,et al.  Homocysteine promotes human endothelial cell dysfunction via site-specific epigenetic regulation of p66shc. , 2011, Cardiovascular research.

[19]  H. Shibuya,et al.  DNA demethylation for hormone-induced transcriptional derepression , 2011, Nature.

[20]  T. Braun,et al.  Epigenetic Modifications of Stem Cells: A Paradigm for the Control of Cardiac Progenitor Cells , 2011, Circulation research.

[21]  Yuri Motorin,et al.  RNA nucleotide methylation , 2011, Wiley interdisciplinary reviews. RNA.

[22]  N. Voelkel,et al.  Suppression of histone deacetylases worsens right ventricular dysfunction after pulmonary artery banding in rats. , 2011, American journal of respiratory and critical care medicine.

[23]  G. Ming,et al.  Hydroxylation of 5-Methylcytosine by TET1 Promotes Active DNA Demethylation in the Adult Brain , 2011, Cell.

[24]  E. Paquet,et al.  The Journal of Experimental Medicine CORRESPONDENCE , 2005 .

[25]  Chuan He,et al.  Grand challenge commentary: RNA epigenetics? , 2010, Nature chemical biology.

[26]  J. Ordovás,et al.  Epigenetics and cardiovascular disease , 2010, Nature Reviews Cardiology.

[27]  Gene Kim,et al.  Epigenetic Attenuation of Mitochondrial Superoxide Dismutase 2 in Pulmonary Arterial Hypertension: A Basis for Excessive Cell Proliferation and a New Therapeutic Target , 2010, Circulation.

[28]  H. Schöler,et al.  Dynamic link of DNA demethylation, DNA strand breaks and repair in mouse zygotes , 2010, The EMBO journal.

[29]  Yoshiyuki Sakaki,et al.  Small RNA class transition from siRNA/piRNA to miRNA during pre-implantation mouse development , 2010, Nucleic acids research.

[30]  M. Pellegrini,et al.  Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency , 2010, Nature.

[31]  A. Abbott.  Project set to map marks on genome , 2010, Nature.

[32]  A. Devlin,et al.  Hepatic acyl-coenzyme a:cholesterol acyltransferase-2 expression is decreased in mice with hyperhomocysteinemia. , 2010, The Journal of nutrition.

[33]  Orian S. Shirihai,et al.  The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α , 2010, Cell.

[34]  T. Down,et al.  Differential DNA Methylation Correlates with Differential Expression of Angiogenic Factors in Human Heart Failure , 2010, PloS one.

[35]  H. Yasuda,et al.  Regulation of the osteoblast-specific transcription factor Osterix by NO66, a Jumonji family histone demethylase , 2009, The EMBO journal.

[36]  Cassandra Willyard.  The saving switch , 2010, Nature Medicine.

[37]  Albert Jeltsch,et al.  Cyclical DNA methylation of a transcriptionally active promoter , 2008, Nature.

[38]  K. Morris.  RNA-directed transcriptional gene silencing and activation in human cells. , 2009, Oligonucleotides.

[39]  Daniel F. Gudbjartsson,et al.  Parental origin of sequence variants associated with complex diseases , 2009, Nature.

[40]  Lee E. Edsall,et al.  Human DNA methylomes at base resolution show widespread epigenomic differences , 2009, Nature.

[41]  Danny Reinberg,et al.  Histones: annotating chromatin. , 2009, Annual review of genetics.

[42]  S. McMahon,et al.  Biochemical pathways that regulate acetyltransferase and deacetylase activity in mammalian cells. , 2009, Trends in biochemical sciences.

[43]  M. Butler.  Genomic imprinting disorders in humans: a mini-review , 2009, Journal of Assisted Reproduction and Genetics.

[44]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[45]  R. Rozen,et al.  Hyperhomocysteinemia is associated with hypertriglyceridemia in mice with methylenetetrahydrofolate reductase deficiency. , 2009, Molecular genetics and metabolism.

[46]  Shu-ren Wang,et al.  Hypermethylation of estrogen receptor-alpha gene in atheromatosis patients and its correlation with homocysteine. , 2009, Pathophysiology : the official journal of the International Society for Pathophysiology.

[47]  E. Li,et al.  KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints , 2009, Nature.

[48]  A. Perna,et al.  Epigenetics in hyperhomocysteinemic states. A special focus on uremia. , 2009, Biochimica et biophysica acta.

[49]  M. Capogrossi,et al.  NO sparks off chromatin: tales of a multifaceted epigenetic regulator. , 2009, Pharmacology & therapeutics.

[50]  M. Turunen,et al.  Epigenetics and atherosclerosis. , 2009, Biochimica et biophysica acta.

[51]  Peter Fraser,et al.  Emerging similarities in epigenetic gene silencing by long noncoding RNAs , 2009, Mammalian Genome.

[52]  Z. Massy,et al.  PROGRESS IN UREMIC TOXIN RESEARCH: Hyperhomocysteinemia in Uremia—A Red Flag in a Disrupted Circuit , 2022 .

[53]  Tatjana Buklijas,et al.  Epigenetic mechanisms that underpin metabolic and cardiovascular diseases , 2009, Nature Reviews Endocrinology.

[54]  Montgomery Slatkin,et al.  Epigenetic Inheritance and the Missing Heritability Problem , 2009, Genetics.

[55]  C. Bloomfield,et al.  MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. , 2009, Blood.

[56]  S. Napoli,et al.  Promoter‐specific transcriptional interference and c‐myc gene silencing by siRNAs in human cells , 2009, The EMBO journal.

[57]  Robert S Illingworth,et al.  CpG islands – ‘A rough guide’ , 2009, FEBS letters.

[58]  M. Hanson,et al.  Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. , 2009, The Journal of nutrition.

[59]  J. Loscalzo,et al.  Quo Vadis: Whither Homocysteine Research? , 2009, Cardiovascular Toxicology.

[60]  K. Ørstavik.  X chromosome inactivation in clinical practice , 2009, Human Genetics.

[61]  R. Codd,et al.  Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A. , 2009, The international journal of biochemistry & cell biology.

[62]  I. Pogribny,et al.  DNA hypomethylation in the origin and pathogenesis of human diseases , 2009, Cellular and Molecular Life Sciences.

[63]  K. Morris,et al.  Promoter targeted small RNAs induce long-term transcriptional gene silencing in human cells , 2009, Nucleic acids research.

[64]  W. Ling,et al.  Betaine supplementation attenuates atherosclerotic lesion in apolipoprotein E-deficient mice , 2009, European journal of nutrition.

[65]  J. Mattick,et al.  Long non-coding RNAs: insights into functions , 2009, Nature Reviews Genetics.

[66]  C. Kuzawa,et al.  Epigenetics and the embodiment of race: Developmental origins of US racial disparities in cardiovascular health , 2009, American journal of human biology : the official journal of the Human Biology Council.

[67]  C. Stefanadis,et al.  Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials. , 2008, European heart journal.

[68]  G. Kelsey,et al.  Transcription is required for establishment of germline methylation marks at imprinted genes. , 2009, Genes & development.

[69]  E. Li,et al.  The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation , 2009, Nature Genetics.

[70]  Jennifer A. Mitchell,et al.  The Air Noncoding RNA Epigenetically Silences Transcription by Targeting G9a to Chromatin , 2008, Science.

[71]  M. Bartolomei,et al.  DNA methyltransferase 1o functions during preimplantation development to preclude a profound level of epigenetic variation. , 2008, Developmental biology.

[72]  Christopher E. Berndsen,et al.  Catalysis and substrate selection by histone/protein lysine acetyltransferases. , 2008, Current opinion in structural biology.

[73]  Daniele Zink,et al.  Nuclear architecture and gene regulation. , 2008, Biochimica et biophysica acta.

[74]  P. Sætrom,et al.  MicroRNA-directed transcriptional gene silencing in mammalian cells , 2008, Proceedings of the National Academy of Sciences.

[75]  H. Blom,et al.  Association between global leukocyte DNA methylation, renal function, carotid intima-media thickness and plasma homocysteine in patients with stage 2-4 chronic kidney disease. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[76]  J. Kumar,et al.  Detection of altered global DNA methylation in coronary artery disease patients. , 2008, DNA and cell biology.

[77]  M. K. Pflum,et al.  Isoform-selective histone deacetylase inhibitors. , 2008, Chemical Society reviews.

[78]  C. Matouk,et al.  Epigenetic Regulation of Vascular Endothelial Gene Expression , 2008, Circulation research.

[79]  W. Liao,et al.  Homocysteine Inhibits Arterial Endothelial Cell Growth Through Transcriptional Downregulation of Fibroblast Growth Factor-2 Involving G Protein and DNA Methylation , 2008, Circulation research.

[80]  Vladimir Benes,et al.  Transient cyclical methylation of promoter DNA , 2008, Nature.

[81]  M. Zavolan,et al.  MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells , 2008, Nature Structural &Molecular Biology.

[82]  J. Jukema,et al.  Epigenetic histone acetylation modifiers in vascular remodelling – new targets for therapy in cardiovascular disease , 2008, Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation.

[83]  R. Wade,et al.  Hypermethylation of Fads2 and Altered Hepatic Fatty Acid and Phospholipid Metabolism in Mice with Hyperhomocysteinemia* , 2007, Journal of Biological Chemistry.

[84]  Hong Wang,et al.  Hyperhomocysteinemia and high-density lipoprotein metabolism in cardiovascular disease , 2007, Clinical chemistry and laboratory medicine.

[85]  W. Bickmore,et al.  G9a Histone Methyltransferase Contributes to Imprinting in the Mouse Placenta , 2007, Molecular and Cellular Biology.

[86]  Hong Wang,et al.  Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin A gene. , 2007, Blood.

[87]  L. Groop,et al.  Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. , 2007, The Journal of clinical investigation.

[88]  B. Walker.  Glucocorticoids and cardiovascular disease. , 2007, European journal of endocrinology.

[89]  Li Zhang,et al.  Genome-Wide Profiling of DNA Methylation Reveals a Class of Normally Methylated CpG Island Promoters , 2007, PLoS genetics.

[90]  Yideng Jiang,et al.  Homocysteine-mediated expression of SAHH, DNMTs, MBD2, and DNA hypomethylation potential pathogenic mechanism in VSMCs. , 2007, DNA and cell biology.

[91]  T. Teerlink,et al.  Global DNA methylation measured by liquid chromatography-tandem mass spectrometry: analytical technique, reference values and determinants in healthy subjects , 2007, Clinical chemistry and laboratory medicine.

[92]  Howard Y. Chang,et al.  Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs , 2007, Cell.

[93]  K. Godfrey,et al.  Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications , 2007, British Journal of Nutrition.

[94]  O. McDonald,et al.  Programming smooth muscle plasticity with chromatin dynamics. , 2007, Circulation research.

[95]  W. Reik.  Stability and flexibility of epigenetic gene regulation in mammalian development , 2007, Nature.

[96]  A. Feinberg.  Phenotypic plasticity and the epigenetics of human disease , 2007, Nature.

[97]  David Sinclair,et al.  Sirtuins in mammals: insights into their biological function. , 2007, The Biochemical journal.

[98]  Shwu‐Yuan Wu,et al.  The Double Bromodomain-containing Chromatin Adaptor Brd4 and Transcriptional Regulation* , 2007, Journal of Biological Chemistry.

[99]  T. Ekström,et al.  Impact of inflammation on epigenetic DNA methylation – a novel risk factor for cardiovascular disease? , 2007, Journal of internal medicine.

[100]  E. Schaefer,et al.  Hypertriglyceridemia and cardiovascular risk reduction. , 2007, Clinical therapeutics.

[101]  Michael B. Stadler,et al.  Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome , 2007, Nature Genetics.

[102]  I. Bogdarina,et al.  Epigenetic Modification of the Renin-Angiotensin System in the Fetal Programming of Hypertension , 2007, Circulation research.

[103]  T. Miyata,et al.  The role of CpG methylation in cell type-specific expression of the aquaporin-5 gene. , 2007, Biochemical and biophysical research communications.

[104]  T. Kouzarides.  Chromatin Modifications and Their Function , 2007, Cell.

[105]  J. Kohlhase,et al.  Confirmation of EP300 gene mutations as a rare cause of Rubinstein–Taybi syndrome , 2007, European Journal of Human Genetics.

[106]  Pierre-Olivier Angrand,et al.  The control of histone lysine methylation in epigenetic regulation. , 2007, Biochimie.

[107]  J. Issa,et al.  Epigenetic changes in estrogen receptor beta gene in atherosclerotic cardiovascular tissues and in-vitro vascular senescence. , 2007, Biochimica et biophysica acta.

[108]  W. Reik,et al.  A developmental window of opportunity for imprinted gene silencing mediated by DNA methylation and the Kcnq1ot1 noncoding RNA , 2007, Mammalian Genome.

[109]  N. Belyaev,et al.  BRG1 Chromatin Remodeling Activity Is Required for Efficient Chromatin Binding by Repressor Element 1-silencing Transcription Factor (REST) and Facilitates REST-mediated Repression* , 2006, Journal of Biological Chemistry.

[110]  J. Kornhuber,et al.  Homocysteine regulates expression of Herp by DNA methylation involving the AARE and CREB binding sites. , 2006, Experimental cell research.

[111]  R. Hui,et al.  Hyperhomocysteinemia Decreases Circulating High-Density Lipoprotein by Inhibiting Apolipoprotein A-I Protein Synthesis and Enhancing HDL Cholesterol Clearance , 2006, Circulation research.

[112]  John J Rossi,et al.  Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells , 2006, Nature Structural &Molecular Biology.

[113]  R. Chakrabarti,et al.  Role of PPAR in cardiovascular diseases. , 2006, Recent patents on cardiovascular drug discovery.

[114]  Paul Tempst,et al.  JHDM2A, a JmjC-Containing H3K9 Demethylase, Facilitates Transcription Activation by Androgen Receptor , 2006, Cell.

[115]  L. Poston,et al.  Folate Supplementation During Pregnancy Improves Offspring Cardiovascular Dysfunction Induced by Protein Restriction , 2006, Hypertension.

[116]  Robin Holliday,et al.  Epigenetics: A Historical Overview , 2006, Epigenetics.

[117]  A. Devlin,et al.  ApoA-I: a missing link between homocysteine and lipid metabolism? , 2006, Circulation research.

[118]  R. Rozen,et al.  Elevated Homocysteine Reduces Apolipoprotein A-I Expression in Hyperhomocysteinemic Mice and in Males With Coronary Artery Disease , 2006, Circulation research.

[119]  H. Erdjument-Bromage,et al.  Histone demethylation by a family of JmjC domain-containing proteins , 2006, Nature.

[120]  R. Castro,et al.  Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: An overview , 2006, Journal of Inherited Metabolic Disease.

[121]  M. Niculescu,et al.  Dietary choline deficiency alters global and gene‐specific DNA methylation in the developing hippocampus of mouse fetal brains , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[122]  Cyrus Martin,et al.  The diverse functions of histone lysine methylation , 2005, Nature Reviews Molecular Cell Biology.

[123]  R. Ferrier,et al.  Pulkovo Observatory and the National Observatory Movement: An Historical Overview , 1990 .

[124]  Antoine H. F. M. Peters,et al.  LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription , 2005, Nature.

[125]  T. Roseboom,et al.  Prenatal exposure to the Dutch famine and disease in later life: an overview. , 2005, Reproductive toxicology.

[126]  T. Spector,et al.  Epigenetic differences arise during the lifetime of monozygotic twins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[127]  A. Devlin,et al.  Tissue-specific Changes in H19 Methylation and Expression in Mice with Hyperhomocysteinemia* , 2005, Journal of Biological Chemistry.

[128]  M. Hanson,et al.  Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. , 2005, The Journal of nutrition.

[129]  Jeffrey S. Robinson,et al.  Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. , 2005, Physiological reviews.

[130]  K. Namekata,et al.  Abnormal Lipid Metabolism in Cystathionine β-Synthase-deficient Mice, an Animal Model for Hyperhomocysteinemia* , 2004, Journal of Biological Chemistry.

[131]  Antony V. Cox,et al.  DNA Methylation Profiling of the Human Major Histocompatibility Complex: A Pilot Study for the Human Epigenome Project , 2004, PLoS biology.

[132]  D. Barker.  The developmental origins of well-being. , 2004, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[133]  S. Frede,et al.  Hypoxia‐induced erythropoietin expression in human neuroblastoma requires a methylation free HIF‐1 binding site , 2004, Journal of cellular biochemistry.

[134]  Michael J Meaney,et al.  Epigenetic programming by maternal behavior , 2004, Nature Neuroscience.

[135]  Esteban Ballestar,et al.  DNA Methylation Polymorphisms Precede Any Histological Sign of Atherosclerosis in Mice Lacking Apolipoprotein E* , 2004, Journal of Biological Chemistry.

[136]  Takashi Nakamura,et al.  Methylation in the Core-promoter Region of the Chondromodulin-I Gene Determines the Cell-specific Expression by Regulating the Binding of Transcriptional Activator Sp3* , 2004, Journal of Biological Chemistry.

[137]  R. Rozen,et al.  Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice. , 2004, Blood.

[138]  R. Hoffman,et al.  Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. , 2003, Blood.

[139]  E. Li,et al.  Establishment and Maintenance of Genomic Methylation Patterns in Mouse Embryonic Stem Cells by Dnmt3a and Dnmt3b , 2003, Molecular and Cellular Biology.

[140]  R. Castro,et al.  Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. , 2003, Clinical chemistry.

[141]  M. D'Esposito,et al.  Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia , 2003, The Lancet.

[142]  Nigel Thrift,et al.  A Rough Guide , 2003 .

[143]  Alan A Jackson,et al.  Increased systolic blood pressure in rats induced by a maternal low-protein diet is reversed by dietary supplementation with glycine. , 2002, Clinical science.

[144]  C. Napoli,et al.  The fetal origins of atherosclerosis: maternal hypercholesterolemia, and cholesterol‐lowering or antioxidant treatment during pregnancy influence in utero programming and postnatal susceptibility to atherogenesis , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[145]  D. Girelli,et al.  A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[146]  Hong Wang,et al.  Cyclin A transcriptional suppression is the major mechanism mediating homocysteine-induced endothelial cell growth inhibition. , 2002, Blood.

[147]  Rudolf Jaenisch,et al.  Chromosomal silencing and localization are mediated by different domains of Xist RNA , 2002, Nature Genetics.

[148]  Gangning Liang,et al.  Cooperativity between DNA Methyltransferases in the Maintenance Methylation of Repetitive Elements , 2002, Molecular and Cellular Biology.

[149]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[150]  Yuan-Yuan Shi,et al.  Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. , 2001, The Journal of clinical investigation.

[151]  K. Godfrey,et al.  Fetal programming and adult health , 2001, Public Health Nutrition.

[152]  I. Pogribny,et al.  Increase in Plasma Homocysteine Associated with Parallel Increases in Plasma S-Adenosylhomocysteine and Lymphocyte DNA Hypomethylation* , 2000, The Journal of Biological Chemistry.

[153]  J. Qin,et al.  Both corepressor proteins SMRT and N‐CoR exist in large protein complexes containing HDAC3 , 2000, The EMBO journal.

[154]  J. Mason,et al.  Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[155]  C. Allis,et al.  The language of covalent histone modifications , 2000, Nature.

[156]  R. Evans,et al.  Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression. , 2000, Genes & development.

[157]  D. Haber,et al.  DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development , 1999, Cell.

[158]  J. Issa,et al.  Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system. , 1999, Cardiovascular research.

[159]  E. Ballestar,et al.  Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation , 1999, Nature Genetics.

[160]  A. Bird,et al.  Identification and Characterization of a Family of Mammalian Methyl-CpG Binding Proteins , 1998, Molecular and Cellular Biology.

[161]  Colin A. Johnson,et al.  Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex , 1998, Nature.

[162]  S. Langley-Evans,et al.  Early administration of angiotensin-converting enzyme inhibitor captopril, prevents the development of hypertension programmed by intrauterine exposure to a maternal low-protein diet in the rat. , 1998, Clinical science.

[163]  蔡哲嘉,et al.  Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine , 1997 .

[164]  Raoul C. M. Hennekam,et al.  Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP , 1995, Nature.

[165]  H. Leonhardt,et al.  A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei , 1992, Cell.

[166]  M. Szyf,et al.  The mouse DNA methyltransferase 5'-region. A unique housekeeping gene promoter. , 1992, The Journal of biological chemistry.

[167]  M. Primig,et al.  Reversible methylation and inactivation of marker genes in sequentially transformed tobacco plants , 1989, The EMBO journal.

[168]  A. Bird.  CpG-rich islands and the function of DNA methylation , 1986, Nature.

[169]  A. Bird.  DNA methylation and the frequency of CpG in animal DNA. , 1980, Nucleic acids research.