Crosstalk to Histone Arginine Methylation

组蛋白精氨酸甲基化的串扰

基本信息

批准号：
10582055
负责人：
DAVID SHECHTER
金额：
$ 16.52万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2023-08-31
项目状态：
已结题

项目摘要

PARENT AWARD ABSTRACT Eukaryotic gene expression requires both transcription factor binding to DNA and histone post-translational modifications (PTMs). In many cases, how these PTMs are mechanistically connected to transcription are still unclear. Transcription factor binding to chromatin–such as by growth factors like TGF or by the hormone-in- ducible glucocorticoid receptor (GR)–initiates transcription. Histone acetylation is transiently deposited on chro- matin during transcriptional activation and during ongoing transcription. In contrast, histone arginine methyla- tion–lasting for days–is a stable PTM. The two major protein arginine methyltransferases, PRMT1 and 5, are regulated by substrate acetylation and phosphorylation. Studying this PTM crosstalk will illuminate how chro- matin environments are transformed to establish and maintain gene expression. We can now transform our understanding of how inducible transcription factor binding works together with both dynamic and long-lasting PTMs to encode transcriptional programs. We hypothesize that PRMT1 and PRMT5 link inducible transcrip- tional activation to a persistent chromatin environment. This hypothesis is compatible with a feed-forward model of chromatin state maintenance, transferring gene activation through multiple histone PTMs. We will test this hypothesis in the following specific aims: 1) How is stable histone arginine methylation regulated by transi- ent PTMs? We will determine biochemical, enzymatic and structural mechanisms of PRMT1 and PRMT5 regu- lation by histone substrate PTMs, like acetylation and phosphorylation. 2) How do transient histone PTMs co- operate with PRMTs to regulate transcription? We will determine how PRMT1 or PRMT5 activity coupled with histone phosphorylation or acetylation affects inducible transcription. 3) Does inducible transcription establish a persistent chromatin environment? We will determine if inducible transcription is persistent past removal of the initial stimulus. The ultimate goal and overall impact of this proposed project is to determine how transcriptional and chromatin-based memory is established and maintained by combinatorial histone modifications. This study will provide mechanistic insight for the clinically critical glucocorticoid signaling pathways, and it will build new understanding of the understudied, but druggable, arginine methyltransferase family. This project will move the field forward in the following ways: 1) it will establish a new paradigm reconciling the long-standing debates over the role of histone PTMs in relationship to transcription factors in transcriptional regulation; 2) we will un- derstand the biochemical mechanisms and biological implications of crosstalk between transient histone PTMs and stable histone arginine methylation; 3) we will understand how hormone-inducible chromatin environments are both established and maintained.

家长奖摘要真核基因表达都需要转录因子与DNA和Hisstone翻译后的结合修改（PTMS）。在许多情况下，这些PTM如何机械连接到转录仍然是不清楚。转录因子与染色质结合，例如通过TGF或Horsene-In-In-的生长因子结合可糖皮质激素受体（GR） - 引发转录。组蛋白乙酰化瞬时沉积在chro- 转录激活和正在进行的转录过程中的麦廷。相反，组蛋白精氨酸甲基持续数天 - 是稳定的PTM。两个主要蛋白精氨酸甲基转移酶Prmt1和5是受底物乙酰化和磷酸化调节。研究此PTM串扰将阐明如何 Mattin环境被转化以建立和维持基因表达。我们现在可以改变我们的了解诱导转录因子结合如何与动态和持久的结合一起工作 PTMS用于编码转录程序。我们假设PRMT1和PRMT5链接可诱导的转录本- 持续的染色质环境激活。该假设与进料兼容染色质状态维持的模型，通过多个Hisstone PTM转移基因激活。我们将测试在以下特定目的中的这一假设：1）稳定的组蛋白精氨酸甲基化如何受到跨性别调节 ENT PTMS？我们将确定PRMT1和PRMT5的生化，酶和结构机制由组蛋白底物PTM（例如乙酰化和磷酸化）铺设。 2）瞬态组蛋白PTMS如何共同使用PRMT进行调节转录？我们将确定PRMT1或PRMT5活动如何与组蛋白磷酸化或乙酰化会影响诱导转录。 3）可诱导转录建立持续的染色质环境？我们将确定诱导型转录是否是持续删除的初始刺激。该拟议项目的最终目标和整体影响是确定转录方式通过组合的Hisstone修饰，基于染色质的记忆是建立和维护的。这项研究将为临床上关键的糖皮质激素信号通路提供机械洞察力，并将建立新的了解该理解但可吸毒的精氨酸甲基转移酶家族。这个项目将移动通过以下方式向前发展：1）它将建立一个新的范式来调和长期的辩论组蛋白PTM与转录因子在转录调控中的作用； 2）我们将不提出了瞬时组蛋白PTMS之间串扰的生化机制和生物学意义和稳定的组蛋白精氨酸甲基化； 3）我们将了解马龙诱导的染色质环境都建立和维护。