disruption of histone modification and carm1 recruitment by arsenic represses transcription at glucocorticoid receptor-regulated promoters中断的组蛋白修饰和carm1招聘砷在糖皮质激素receptor-regulated启动子的转录压制.pdfVIP

Disruption of Histone Modification and CARM1 Recruitment by Arsenic Represses Transcription at Glucocorticoid Receptor-Regulated Promoters 1 1¤a 2,3¤b 1,3 Fiona D. Barr , Lori J. Krohmer , Joshua W. Hamilton , Lynn A. Sheldon * 1 Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire, 2 Department of Pharmacology Toxicology, Dartmouth Medical School, Hanover, New Hampshire, 3 Center for Environmental Health Sciences, Dartmouth Medical School, Hanover, New Hampshire Abstract Chronic exposure to inorganic arsenic (iAs) found in the environment is one of the most significant and widespread environmental health risks in the U.S. and throughout the world. It is associated with a broad range of health effects from cancer to diabetes as well as reproductive and developmental anomalies. This diversity of diseases can also result from disruption of metabolic and other cellular processes regulated by steroid hormone receptors via aberrant transcriptional regulation. Significantly, exposure to iAs inhibits steroid hormone-mediated gene activation. iAs exposure is associated with disease, but is also used therapeutically to treat specific cancers complicating an understanding of iAs action. Transcriptional activation by steroid hormone receptors is accompanied by changes in histone and non-histone protein post-translational modification (PTM) that result from the enzymatic activity of coactivator and corepressor proteins such as GRIP1 and CARM1. This study addresses how iAs represses steroid receptor-regulated gene transcription. PTMs on histones H3 and H4 at the glucocorticoid receptor (GR)-activated mouse mammary tumor virus (MMTV) promo