Contribution of Non-Coding Genome to Placental Defects: The Establishment & Application of a Novel Tool to Reliably Map & Quantify Active Enhancers
Human body consists of many different cell types, each of them carrying the same genes yet having a distinct morphology and function. This is possible because different genes are activated in different cells, as a consequence of gene regulation. Gene regulation is itself encoded in the genome, and involves genes and proteins which regulate other genes by binding to non-coding regulatory elements some distance away from the genes, thereby turning genes on in some cells and off in others. These cell-specific regulatory elements comprise large part of the human genome. Because both gene-coding and regulatory sequences are important for normal function, the disease-causing mutations can occur in the protein-coding genes as well as in the regulatory regions. Yet we often do not know where the regulatory elements are, which genes they affect, and in which cells or tissues they act.
In this study, we will implement a very efficient method to screen for such regulatory regions, active in placenta. Placental defects cause many common pregnancy complications, among them preeclampsia and preterm birth. Previous studies have identified mutations, which often occur in diseased individuals. Many of these mutations are in the non-coding regions, therefore understanding what these regions do will help us understand and potentially address their defects. Tissue-specificity of regulatory regions makes them particularly interesting treatment targets. Targeting coding genes often generates side effects, because genes are used repeatedly in many tissues of an organism. Identifying causal mutations in regulatory regions can thus open possibilities for treatments because regulatory modification appears more accessible and has fewer side effects, than the modification of a multifunctional protein.