ReviewGene to screenEpigenetic code and potential epigenetic-based therapies against chronic diseases in developmental origins
Introduction
Increasing epidemiological evidence suggests that maternal nutrition and environmental factors in early development periods play an important part in susceptibility of disease in later life 1, 2. In the mid-1990s, Barker et al. coined the hypothesis of ‘fetal origins of adult diseases’ [3], indicating that intrauterine factors and/or maternal nutritional status have long-term programming effects on fetal development, ultimately leading to increased susceptibility of chronic diseases. This concept has been supported by a growing body of studies on low birth weight (LBW) 4, 34, intrauterine growth retardation (IUGR) [5], premature birth [6] and maternal malnutrition [7] associated with increased risks of chronic diseases later in life in humans.
Although underlying mechanisms involved in molecular pathogenesis of chronic diseases in developmental origins are under investigation, it is accepted that changes in epigenetic modifications or code are early significant events in the pathogenesis of chronic diseases. Epigenetics, an emerging subject in the field of genetics, means heritable changes in cellular phenotype and gene expression that are not involved in DNA sequences [8]. During the past decade, the epigenetic code has been identified as a key regulator of gene expression [9], and therefore is likely to play major parts in transcriptional regulations, genome stability, cell proliferation and embryonic development, among others. Classically, major epigenetic marks contain DNA methylation, histone modifications, genomic imprinting and noncoding RNA.
DNA methylation is a characterized chemical modification of chromatin in all unicellular and multicellular organisms. In mammals, DNA methylation predominantly occurs at cytosine-C5 in the context of CpG dinucleotides, and is established and maintained by three active DNA methyltransferases 10, 11. DNA methylation is a dynamic biological process and undergoes dynamic reprogramming during gametogenesis and early embryogenesis in mammals [12]. As a key regulatory mechanism in epigenetics, DNA methylation has regulatory roles in normal and abnormal cellular processes, and is essential for embryonic development, genomic imprinting, X-inactivation and gene repression.
In eukaryotes, the nucleosome is the basic repeating unit of chromatin, which is an octamer comprising four histones: H2A, H2B, H3, H4, and 146 bp of DNA wrapped around the histones [13]. Typically, each histone harbors an amino-terminal 20–40 residue ‘tail’. These histone tails provide sites for an enormous number of reversible post-translational modifications, including methylation, acetylation and phosphorylation [14]. These covalent modifications in nucleosomes are known as histone modifications with well-known roles in alteration of chromatin structures to influence patterns of gene expression [15].
In recent years, increasing evidence indicates that noncoding RNAs (ncRNAs) are important in controlling multiple epigenetic phenomena and regulating differentiation and development in eukaryotes [16]. MicroRNAs (miRNAs), a class of small ncRNAs, are ∼22 nucleotides long and crucial regulators in the epigenetic control of gene expression and cell differentiation [17]. Commonly, miRNAs, as relatively negative regulators of gene expression, have been associated with a variety of diseases, including coronary disease 18, 19.
Genomic imprinting, a classic epigenetic mark by which certain genes can be expressed in a parent-specific manner, is acquired during gametogenesis and maintained during pre-implantation development [20]. Genomic imprinting has a crucial influence on the regulation of mammalian development and correlates with pathophysiologic mechanisms in many human diseases 21, 52. In eukaryotes, interactions and crosstalk among various epigenetic marks are essential in regulating chromatin structures and gene expression.
As mentioned above, early embryogenesis in utero is a crucial event for the establishment of epigenetic information, especially DNA methylation. However, it also provides a chance for prenatal stress that could affect the establishment of DNA methylation during crucial developmental periods. Indeed, the changes of epigenetic modifications caused by prenatal stress, including prenatal malnutrition [25], and hypoxia [22], as well as other intrauterine insults [23], have crucial programming roles in the postnatal pathological processes of chronic diseases (Fig. 1). In this article, we give a short review of recent findings of epigenetic mechanisms on developmental origins of several human chronic diseases, and try to provide an overview of the current epigenetic-based strategies applied in early prevention, diagnosis and possible therapies against chronic diseases (Table 1).
Section snippets
Epigenetic code and the developmental programming of cardiovascular and metabolic diseases
Starting 20 years ago, there has been a steady growth in the number of laboratories and investigators involved in the investigation on developmental origin of cardiovascular diseases (CVDs) and metabolic syndrome (MS). And considerable evidence demonstrates that the epigenetic regulation of gene expression is crucial in prenatal-stress-induced fetal programming of CVDs 22, 24. MS is the name for a group of health problems that occur when hormones or other chemicals fail to interact properly in
Neural and mental disorders
Neural and mental disorders are diseases of the nervous system, including Parkinson's disease, schizophrenia, autism spectrum disorders (ASDs) and other disorders affecting the central and peripheral nervous system. Recent studies have shown that neural and mental disorders are linked with early life stress in utero, including insufficient nutrition, maternal use of psychiatric drugs and mental stress during pregnancy 61, 62, 63. For example, accumulated evidence indicates that methyl CpG
Concluding remarks
Along with the studies on molecular pathogenesis of chronic diseases, roles of epigenetic codes in developmental origins of chronic diseases, and more details in epigenetic changes in diseases with developmental origins, are going to be discovered in the near future, because more studies are going on in that field. In addition, clinical and basic science researchers have finally realized that early intervention could be the top strategy in prevention of chronic diseases. Meanwhile, based on the
Acknowledgments
This work was supported partly by Grants 2013BAI04B05 and 2012CB947600; National Nature & Science Foundation of China (81030006, 81320108006); and Jiangsu key discipline/Laboratory and ‘Chuang XinTuan Dui’ funds. We thank technical support from Encode Genomics Bio-technology, Ltd. We would like to apologize that this mini-review cannot include all interesting and important work and publications regarding epigenetic alterations related chronic diseases owing to space constraints.
References (79)
The association of birth weight with cardiovascular risk factors and mental problems among Iranian school-aged children: the CASPIAN-III study
Nutrition
(2014)Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children
J Allergy Clin. Immunol.
(2014)- et al.
Epigenetic mechanisms linking early nutrition to long term health
Best Pract. Res. Clin. Endocrinol. Metab.
(2012) - et al.
Role of covalent modifications of histones in regulating gene expression
Gene
(1999) Long noncoding RNAs with enhancer-like function in human cells
Cell
(2010)miR-204/miR-211 downregulation contributes to the Candidemia-induced kidney injuries via derepression of Hmx1 expression
Life Sci.
(2014)MicroRNAs regulate several functions of normal tissues and malignancies
Taiwan J. Obstet. Gynecol.
(2013)Genomic imprinting and mammalian development
Placenta
(1996)Nicotinamide supplementation induces detrimental metabolic and epigenetic changes in developing rats
Br. J. Nutr.
(2013)Influence of angiotensin II type 1 receptor-associated protein on prenatal development and adult hypertension after maternal dietary protein restriction during pregnancy
J. Am. Soc. Hypertens.
(2012)
Role of angiotensin II type-1 and type-2 receptors on vascular smooth muscle cell growth and glucose metabolism in diabetic rats
Diabetes Res. Clin. Pract.
microRNA involvement in developmental and functional aspects of the nervous system and in neurological diseases
Neurosci. Lett.
Association between birth characteristics and coronary disease risk factors among fifth graders
J. Pediatr.
Genome wide DNA methylation profiling for epigenetic alteration in coronary artery disease patients
Gene
BET acetyl-lysine binding proteins control pathological cardiac hypertrophy
J. Mol. Cell. Cardiol.
Inhibition of histone deacetylation protects wildtype but not gelsolin-deficient mice from ischemic brain injury
Exp. Neurol.
Prenatal origin of obesity and their complications: gestational diabetes, maternal overweight and the paradoxical effects of fetal growth restriction and macrosomia
Reprod. Toxicol.
The impact of maternal consumption of cafeteria diet on reproductive function in the offspring
Physiol. Behav.
Prenatal smoking might not cause attention-deficit/hyperactivity disorder: evidence from a novel design
Biol. Psychiatry
An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders
Cell
DZNep, inhibitor of S-adenosylhomocysteine hydrolase, down-regulates expression of SETDB1 H3K9me3 HMTase in human lung cancer cells
Biochem. Biophys. Res. Commun.
Relationships between nutrition during pregnancy and subsequent infant and child development
Obstet. Gynecol. Surv.
Association of intrauterine cigarette smoke exposure with indices of fetal lung maturation
Obstet. Gynecol.
The intrauterine and early postnatal origins of cardiovascular disease and chronic bronchitis
J. Epidemiol. Community Health
Fetal growth restriction and pulmonary hypertension in premature infants with bronchopulmonary dysplasia
J. Perinatol.
Epigenetics: an overview
Dev. Genet.
Epigenetics: regulation through repression
Science
Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b
Mol. Cell Biol.
Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylation
Nucleic Acids Res.
DNA methylation dynamics during the mammalian life cycle
Philos. Trans. R Soc. Lond. B Biol. Sci.
A low resolution structure for the histone core of the nucleosome
Nature
The language of covalent histone modifications
Nature
Human coronary heart disease: importance of blood cellular miR-2909 RNomics
Mol. Cell. Biochem.
Genomic imprinting and human disease
Essays Biochem.
Promoter methylation of Egr-1 site contributes to fetal hypoxia-mediated PKC(gene repression in the developing heart
Am. J. Physiol. Regul. Integr. Comp. Physiol.
Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring
Int. J. Obes. (Lond.)
Effects of early-life environment and epigenetics on cardiovascular disease risk in children: highlighting the role of twin studies
Pediatr. Res.
Maternal undernutrition programs tissue-specific epigenetic changes in the glucocorticoid receptor in adult offspring
Endocrinology
Effects of a high-fat diet exposure in utero on the metabolic syndrome-like phenomenon in mouse offspring through epigenetic changes in adipocytokine gene expression
Endocrinology
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