Molecular Regulation of Alternative Splicing by Nuclear Receptors and Coregulators

点击翻译按钮获取中文摘要

The nuclear hormone receptors comprise a superfamily of ligand-activated transcription factors that regulate diverse physiological processes by coordinating patterns of gene expression. Transcriptional activation by a nuclear hormone receptor (NR) depends strongly on its interactions with coactivators and corepressors that either directly or indirectly modify the surrounding chromatin configuration to allow recruitment of the basal transcriptional machinery. While transcriptional activation or repression changes absolute levels of mRNA transcripts, an additional layer of complexity is created in the cell by the alternative splicing of the pre-messenger RNA. Much progress has been made in the field of alternative splicing through the study of RNA binding proteins which are important in reading the "splicing code", relatively little is known about how ligand-dependent transcriptional activation and alternative splicing are controlled in cells. Recently, we identified ARGLU1 as a glucocorticoid receptor (GR) coactivator and showed that it can affect splicing using in vitro mini-gene assays. Since, GR signaling has been a well studied paradigm for understanding of how nuclear receptors integrate environmental cues and translate them into changes in gene transcription, and ARGLU1 is a novel GR coactivator involved in splicing, we decided to uses these two proteins as a model to investigate cell-specific novel mechanisms of ligand-dependent transcriptional control. With recent advances in next generation sequencing technology we can now study the endogenous role of these NR binding proteins in alternative splicing. This research program will examine the molecular mechanisms by which members of the NR superfamily help promote transcriptional diversity by coordinating ligand-dependent transcriptional activation with alternative splicing. Because over 90% of human genes are estimated to undergo alternative splicing, understanding how nuclear receptors contribute to the transcriptional diversity at the molecular level is essential for understanding how NRs function in cell and tissue-specific contexts.