DNA methylation: an epigenetic risk factor in preterm birth

Abstract

Spontaneous preterm birth (PTB; birth prior to 37 weeks of gestation) is a complex phenotype with multiple risk factors that complicate our understanding of its etiology. A number of recent studies have supported the hypothesis that epigenetic modifications such as DNA methylation induced by pregnancy-related risk factors may influence the risk of PTB or result in changes that predispose a neonate to adult-onset diseases. The critical role of timing of gene expression in the etiology of PTB makes it a highly relevant disorder in which to examine the potential role of epigenetic changes. Because changes in DNA methylation patterns can result in long-term consequences, it is of critical interest to identify the epigenetic patterns associated with adverse pregnancy outcomes. This review examines the potential role of DNA methylation as a risk factor for PTB and discusses several issues and limitations that should be considered when planning DNA methylation studies.

Figure 1.

This figure provides a comprehensive schema of the processes that impact preterm birth (PTB) from a general level (outer circle) to the final steps (inner circle). These factors can potentially function independently or can interact to affect PTB. Each risk factor operates via multiple related clinical manifestations (middle circle), encompassing overlapping and often redundant biomolecules, culminating in a final effector cascade (innermost circle). Preterm birth is effectively a syndrome of multiple disease processes. These risk factors and disease processes are mediated by immune and inflammatory processes that produce uterotonins (Prostaglandins - PGs) and stimulate decidual activation, myometrial contractility, fetal membrane weakening and rupture, and cervical ripening and dilatation, culminating in premature labor and delivery. These pathologic processes are initiated by well-characterized risk factors (outer circle). *The environment alone may consist of multitude of exogenous factors not limited to a single factor. Environmental risk factors may lead to epigenetic changes, resulting in long-term alterations in gene expression that increase the risk of adult-onset diseases. Epigenetic changes can also occur as a result of risk associated clinical manifestations and also due to interventions, if any, at this stage. Unlike static genetic risk factors, epigenetic changes can happen at multiple levels as indicated in the figure.