Amnion epithelial cells stained for Kv1.5, a glucocorticoid regulated voltage gated potassium channel
Glucocorticoid Signaling in Fetal Membranes
Glucocorticoids exist naturally in the body and cortisol serves as the bodies stress response. Sustained elevated levels of cortisol can lead to health problems such as sleep disturbances, high blood pressure, weight gain, osteoporosis and other side effect. In addition to the bodies natural glucocorticoid system, synthetic glucocorticoids such as dexamethasone and prednisone are some of the most widely prescribed medications globally. Dexamethasone is often given to women with threatened preterm labor. Although primarily an anti-inflammatory compound and labor is seen as an immune inflammatory reaction, dexamethasone has no effect on gestation length. In fact, increasing doses of glucocorticoids may decrease gestation length and increase the likelihood of preterm birth. We think this disconnection is due to the glucocorticoid responses in fetal membranes.
Peaks indicate active regulatory regions overlapping the EEFSEC gene in a STARR-seq assay. Red peaks indicate untreated endometrial stromal fibroblasts and blue peaks show endometrial stromal fibroblasts that have been decidualized by medroxyprogesterone acetate and cyclic AMP.
Noncoding Variation in Preterm Birth
Genome wide association studies often uncover noncoding variants associated with a disease. These variants are hard to interpret and identify a casual mechanism of the disease. These variants are thought to be in regulatory regions that effect the activation of genes nearby or kilobases away. Using the massively parallel reporter assay, STARR-seq, we can identify the regulatory regions at the scale needed to understand genetic associations. This reporter assay transcribes active regulatory regions to combine the power of traditional reporter assays with next generation sequencing. A recently published genome wide association study identified regions associated with preterm birth, We can study these regions in the STARR-seq assay using endometrial stromal fibroblasts, cells that contribute to the mother’s portion of the placenta in pregnancy and have shown to be likely associated with preterm birth. We can identify regions of the genome that have active regulatory activity in association with preterm birth. By combining this data with chromatin conformation data generated by collaborators, we can go beyond the nearest gene approximation to linking regulatory variants to genes they regulate and have a greater understanding of the pathways leading to preterm birth.
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Majoros W, Kim YS, Barrera A, Li F, Wang X, Cunningham S, Johnson G, Guo C, Lowe W, Scholtens D, Hayes G, Reddy T, Allen ; Bayesian Estimation of Genetic Regulatory Effects in High-throughput Reporter Assays. Bioinformatics: 2020 January 15