Epigenetic Regulation by Poly(ADP-ribose) in Response to Arsenite

描述（由申请人提供）： 慢性砷暴露危及数百万人的皮肤改变，外周血管疾病和癌症，包括皮肤癌，肺癌和膀胱癌，部分原因是改变基因表达。越来越多的证据表明，表观遗传机制可以调节基因的激活或沉默。 因此，表观遗传调控可能是砷毒性机制的一部分。聚（ADP-核糖）聚合酶-1（PARP-1）与聚（ADP-核糖）（一种带负电荷的聚合物）共价修饰组蛋白。核小体组蛋白的聚（ADP-核糖基）化改变染色质结构，因此被认为调节染色质模板依赖性过程，包括基因转录。最近，PARP-1已被证明可以调节胁迫诱导的基因转录。 总的假设是，染色质相关的PARP-1与聚（ADP-核糖）共价修饰核小体组蛋白，聚（ADP-核糖基）化组蛋白表观遗传学调节基因转录响应亚砷酸盐。具体目标是：（1）确定多元的层次和模式（2）阐明砷暴露后pADPr-组蛋白水平改变的细胞机制，（3）测定多聚腺苷酸（ADP-核糖基）化的组蛋白对砷暴露的反应。在亚砷酸盐诱导的靶基因的染色质启动子处（ADP-核糖基）化的组蛋白，和（4）确定PARP酶抑制剂对其它亚砷酸盐诱导的表观遗传标记的影响。 这些研究的意义在于为研究组蛋白的多聚ADP-核糖基化可能调控和被调控以实现应激反应基因转录的表观遗传机制提供了新的见解。聚（ADP-核糖基）化的这种机制可能特别适合于促进有效转录活性的突然爆发，因此对环境暴露的结果至关重要。

DESCRIPTION (provided by applicant): Chronic arsenic exposure endangers millions of people with skin alterations, peripheral vascular disease, and cancer, including skin, lung, and bladder cancer by, in part, altering gene expression. Increasing evidence demonstrates that epigenetic mechanisms could regulate gene activation or silencing. Therefore, epigenetic regulation could be a part of the mechanisms for arsenic-induced toxicity. Poly(ADP-ribose) polymerase-1 (PARP-1) covalently modifies histones with poly(ADP-ribose), a negatively charged polymer. Poly(ADP-ribosyl)ation of nucleosomal histones alters chromatin structure and is thus thought to regulate chromatin template-dependent processes including gene transcription. Recently, PARP-1 has been shown to regulate stress-induced gene transcription. The overall hypothesis is that chromatin-associated PARP-1 covalently modifies nucleosomal histones with poly(ADP-ribose), and poly(ADP-ribosyl)ated histone(s) epigenetically regulates gene transcription in response to arsenite. The specific aims are to (1) determine the level and patterns of poly(ADP-ribosyl)ated histones in response to arsenite exposure, (2) elucidate the cellular mechanism that can alter the level of pADPr-histones in response to arsenite, (3) determine poly(ADP-ribosyl)ated histone(s) at the chromatin promoters of arsenite-induced target genes, and (4) determine the impact of a PARP enzymatic inhibitor on other arsenite-induced epigenetic markings. The significance of the proposed studies is to offer new insights into the epigenetic mechanism(s) by which poly(ADP-ribosyl)ation of histone(s) may regulate and be regulated to achieve stress response gene transcription in response to arsenite exposure. This mechanism of poly(ADP-ribosyl)ation may be especially adapted to facilitate sudden bursts of efficient transcription activity and therefore is critical for the outcome of environmental exposure.