Evidence for Epigenetic Changes in the Estrogen Receptor Alpha Promoter in Lymphangioleiomyomatosis (LAM)

Lymphangioleiomyomatosis (LAM) is a rare but often fatal disease, characterized by the abnormal proliferation of smooth muscle cells of the lung. LAM occurs almost exclusively in women and its pathology correlates with mutations in the tuberous sclerosis complex 2 (TSC2) gene and expression of the hormone estrogen. One of the hallmarks of LAM lesions is the anomalous expression of the intracellular receptor for estrogens, ER , and the distinct gender specificity of LAM would support the hypothesis that this anomalous expression of ER plays an essential role in the pathology of the disease. Our previous studies have defined a direct link between the TSC2 gene product tuberin and estrogen signaling through ER . The objectives of this study were to investigate epigenetic changes in the ER promoter as a mechanism for upregulation of ER expression in LAM disease. The results of this study provide evidence for: a) use of multiple ER promoters in human airway smooth muscle cells and LAMassociated cell lines, b) epigenetic changes in the promoter of the ER gene in LAM-associated cell lines and LAM lesions, and c) differential binding of histone deacetylase 1 and methyl-CpG binding proteins in human airway smooth muscle and LAM cells. These studies cumulatively suggest the upregulation of ER expression associated with LAM disease may in part be a consequence of demethylation at the ER promoter.