Long-term low level glucocorticoid exposure induces persistent repression in chromatin.
Environmental exposure to low concentration hormones can have permanent epigenetic effects in animals and humans. The consequence of long-term low concentration glucocorticoid exposure was investigated in cell culture using glucocorticoid responsive genes organized in alternative chromatin structures. The MMTV promoter is induced by short-term glucocorticoid exposure on either an integrated (normal chromatin) or transient (unstructured chromatin) promoter. Longer hormone treatment causes a transient refractory repression of only the integrated promoter. Exposure to low concentrations of hormone for several passages persistently represses the integrated MMTV and endogenous glucocorticoid responsive promoters. The glucocorticoid receptor cannot bind to persistently repressed promoters. Induction by androgens is also inhibited on the repressed MMTV promoter. Similarly, osmotic stress induction of the endogenous Sgk gene is repressed. Persistent repression by glucocorticoids targets glucocorticoid responsive genes using a chromatin-dependent mechanism that disrupts binding of both GR-dependent and GR-independent transcription complexes.
Burkhart
Barbara A
BA
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Ivey
Melissa L
ML
Archer
Trevor K
TK
D002843:Chromatin / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D020868:Gene Silencing / Q000187:drug effects*; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D046912:Multiprotein Complexes / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D002843:Chromatin; D005938:Glucocorticoids; D046912:Multiprotein Complexes; D011965:Receptors, Glucocorticoid