STUDY OF THE GR-MEDIATED EPIGENETIC REGULATION IN LUNG EPITHELIAL CELLS

TRABA, SA; OGARA, MF; ADALI, P; RODRÍGUEZ SEGUÍ, SA

San Carlos de Bariloche

Simposio; 3rd South American Symposium in Signal Transduction and Molecular Medicine; 2015

Under physiological conditions, glucocorticoids (GCs) help to regulate glucose synthesis according to circadian rhythms and to suppress inflammation in response to stress. They are also crucial during fetal development for the maturation of tissues and organs, promoting cellular differentiation. Most notably, they act during late gestation to stimulate surfactant production by the lung. However, abnormally high levels of GCs during pregnancy can permanently alter tissue GC signaling in the fetus, leading to short-term adaptive benefits but increasing the risk of later disease. Pathological increase of GC levels at earlier time points during development can induce premature differentiation of tissue-specific progenitor cells, thus leading to abnormal tissue and organ formation. Such adverse effects have been reported to influence kidney, pancreas, liver, heart and thymus development. Also, despite antenatal corticosteroid treatment is advantageous for overcoming surfactant deficiency, that causes infant respiratory distress syndrome, the treatment of fetuses and preterm infants with high doses of corticosteroids may have considerable long-term side effects also on lung growth. The molecular mechanisms underlying the programming effects of early exposure to GCs include chromatin epigenetic changes that might permanently affect gene expression. In particular, our work aims at understanding how GC-mediated epigenomic changes affect gene expression at shared genes that are relevant for development of glandular epithelial tissues. For this purpose, we used ChIP-seq datasets for H3K4me1 and H3K27ac histone modifications to produce enhancer maps in several tissues, including lung, fetal pancreas, adult pancreatic islets and mammary epithelium. To infer GR-regulated genes in such tissues, we integrated enhancer maps with ChIP-seq genome wide binding profiles for the GR, and transcriptome maps. Using as model the A549 lung epithelial cell line, our work is currently focused in the characterization of enhancer regions in the vicinity of genes that are important for the development of epithelial tissues and how these are regulated by the GR.