Kjersti M. Aagaard, M.D., Ph.D.
Baylor College of Medicine
Obstetrics & Gynecology
One Baylor Plaza
MS: BCM 610
Houston, Texas 77030
Aagaard Laboratory Focus
Epigenetics and the Intrauterine Environment Early modem conception of "genes" as the backbone of inheritance originated with work by Gregor Mendel, a 19th century Austrian monk who studied heredity in pea plants. Mendel's work along with that of Wilhelm Johannsen, Thomas Hunt Morgan, Barbara McClintock, and others led to our understanding of particulate inheritance, or the theory that inherited traits are passed from one generation to the next in discrete units that interact in well-defined ways. Since these early days of our understanding that genes and chromosomes function as the backbone of our genetic heredity, our view of heredity has been written in the language of DNA with the assumption that genetic mutations and changes in the nucleotide backbone have driven most descriptions of how phenotypic traits and diseases are passed down from one generation to another. Yet, recent discoveries in the field of epigenetics --the study of heritable changes in gene function that occur without a change in the DNA sequence --have blurred our thinking and are changing our thoughts about heredity.
Epigenetic mechanisms such as DNA methylation, histone acetylation, and RNA interference, and their effects in gene activation and inactivation, are increasingly understood to have a profound effect in altering an individual's appearance, transmission of a specific congenital abnormality ("birth defect"), and even one's lifetime risk of common diseases such as obesity and cancer. Thus we have arrived at the point in our current understanding that while genomic DNA is the template of our heredity, it is the orchestration and regulation of its expression via epigenetic mechanisms in chromatin remodeling that ultimately results in the complexity and diversity among individuals observed in nature.
According to the fetal origins of adult disease hypothesis, perturbations in utero environment influence the development of diseases later in life. This was first observed to occur in response to maternal nutritional constraints which resulted in a growth restricted infant: these tiny babies later develop profound changes including obesity, insulin resistance, hypertension, heart disease, and lipid disorders. Working in animal models, we and other researchers have shown that these lifelong disease risks occur through the static reprogramming of gene expression via epigenetic alterations in chromatin structure (or changes in the "histone code"). Our current focus in the laboratory is linking epigenetic changes to alterations in the in utero environment which occur in response to common current pregnancy exposures: maternal obesity, maternal tobacco use, and the relative absence of essential nutrients.
Obesity causes substantial social, economic and health burdens. The rate of obesity is escalating disproportionately in children (infants to young adults). This rapid increase is unlikely to be due to environment or genetics alone. Based on previous research, we believe that obesity in part starts when the child was a fetus in utero and occurs because of reprogramming of gene expression caused by the mother's diet and health. In addition, although models of intrauterine growth restriction have been established which demonstrate that fetal alterations in the histone code are involved in the persistence and conveyance of the altered postnatal phenotype, little is known about the effects of a high fat maternal diet and resultant obesity on primate fetal biology. We hypothesized that a high fat diet in non-human primates would induce tissue specific changes in chromatin structure resulting in altered expression of fetal genes critical to the development of childhood and adult diseases. Based on (1) our preliminary data, and (2) emerging evidence that the Clock family of circadian genes functions to orchestrate multiple metabolic processes, a primary focus of our current research resides on the epigenetic modifications in fetal circadian gene expression induced in response to a high fat maternal environment.
We have recently initiated efforts to extend our initial work into a broader realm employing high throughput technology. Accumulating evidence from our laboratory and others suggests that adult metabolic diseases originate in utero, and likely occur through the reprogramming of gene expression via epigenetic changes in chromatin structure (an altered "histone code"). Of interest, we have observed in a rodent transgenerational model of intrauterine growth restriction (IUGR) that a diet supplemented with essential nutrients, yet unaltered in its caloric content, prevents adult metabolic disease and is associated with abrogation of reprogrammed gene expression. Based on our preliminary data, the focus of our extended efforts is to apply developed high throughput technology (comparative epi-genomics and metabolomics) to decipher the primate epi-genome and metabolome in the obese maternal environment and then measure the impact of supplementation on the differentially altered epi-genome and resultant disease. The novel innovation and significance resides within its potential to provide (1) an expanded understanding of the mechanism through which a maternal high fat diet reprograms primate gene expression and (2) a simple intervention (essential nutrient supplementation with neither diet nor behavioral modification) with tremendous potential impact given the current obesity epidemic and the lack of efficacious therapeutics.
Maternal cigarette smoking is considered the single largest modifiable risk factor for intrauterine growth restriction in developed countries. Of the approximately 4000 compounds found in tobacco smoke, long-term adverse effects are largely ascribed to nicotine and the polycyclic aromatic hydrocarbons. Given our observations that fetal growth restriction associated with uteroplacental insufficiency is associated with epigenetic alterations in key determinants of chromatin structure, which regulates whether DNA is amenable to transcriptional regulation, we have developed animal models to examine the effect of nicotine and cigarette exposure in utero on the fetal histone code. We have further performed parallel research in DNA samples from human infants exposed to tobacco smoke in utero, and have observed an additional contribution of specific deletions in fetal metabolic genes (GSTTI). Our current research is focused on the mechanisms by which maternal smoking and subsequent tobacco exposure affects the lifelong health and disease risk of the developing fetus.
Nutritional building blocks, such as methyl groups of 5'-methyl cytosine, are either synthesized de novo in one-carbon metabolism or are supplied from the diet. Given our previous findings demonstrating that fetal growth restriction affects hepatic one-carbon metabolism, we were curious whether the development of adult metabolic diseases could be altered by essential nutrient supplementation. Our initial observations have demonstrated that a diet supplemented with essential nutrients, yet unaltered in its caloric content, prevents adult obesity and insulin resistance in a heritable transgenerational model of fetal growth restriction in rats. Interestingly, this is accompanied by significant alterations in the expression of reprogrammed metabolic genes. Our current efforts are focused on understanding how essential nutrient supplementation prevents adult metabolic diseases, and whether this relates to epigenetic alterations of chromatin structure.
In summary, our laboratory efforts focus on understanding how epigenetic mechanisms are at play in an aberrant intrauterine environment. Advances in our understanding will enable us to treat common adult diseases at potentially their earliest point: in utero fetal development.