Molecular Regulation of Alternative Splicing by Nuclear Receptors and Coregulators

核激素受体包括配体激活的转录因子的超家族，其通过协调基因表达模式来调节多种生理过程。核激素受体（NR）的转录激活强烈依赖于其与辅激活子和辅抑制子的相互作用，辅激活子和辅抑制子直接或间接地修饰周围的染色质构型以允许基础转录机制的募集。 虽然转录激活或抑制会改变mRNA转录物的绝对水平，但前信使RNA的选择性剪接会在细胞中产生额外的复杂性。通过对阅读“剪接密码”的重要RNA结合蛋白的研究，选择性剪接领域取得了很大进展，但对细胞中配体依赖的转录激活和选择性剪接是如何控制的知之甚少。最近，我们鉴定了ARGLU1作为糖皮质激素受体（GR）共激活剂，并表明它可以影响剪接使用体外微型基因测定。由于GR信号已经被充分研究的范式，了解核受体如何整合环境线索，并将其转化为基因转录的变化，和ARGLU1是一种新的GR共激活剂参与剪接，我们决定使用这两种蛋白质作为模型来研究细胞特异性的配体依赖性转录控制的新机制。随着新一代测序技术的最新进展，我们现在可以研究这些NR结合蛋白在选择性剪接中的内源性作用。该研究计划将研究NR超家族成员通过协调配体依赖性转录激活与选择性剪接来帮助促进转录多样性的分子机制。由于超过90%的人类基因估计经历选择性剪接，了解核受体如何在分子水平上促进转录多样性对于了解核受体如何在细胞和组织特异性环境中发挥作用至关重要。

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.