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患有皮肤病变、外周血管疾病和癌症的人，包括皮肤癌、肺癌和膀胱癌，部分原因是改变了基因表达。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)与带负电荷的聚合物聚(ADP-核糖)共价修饰组蛋白。核小体组蛋白的多聚(ADP-核糖基)改变染色质结构，因此被认为调节染色质模板依赖的过程，包括基因转录。最近，PARP-1被证明可以调节应激诱导的基因转录。总体假设是染色质相关的PARP-1与多腺苷二磷酸核糖共价修饰核糖体组蛋白，而多腺苷二磷酸核糖修饰的组蛋白(S)在表观遗传上调节基因转录以响应亚砷酸盐。其具体目的是(1)确定亚砷酸盐诱导的靶基因染色质启动子上聚腺苷二磷酸核糖基化组蛋白的水平和模式，(2)阐明亚砷酸盐诱导的pADPr-组蛋白水平改变的细胞机制，(3)确定亚砷酸盐诱导的靶基因染色质启动子处的聚腺苷二磷酸核糖基化组蛋白(S)，以及(4)确定PARP酶抑制剂对亚砷酸盐诱导的其他表观遗传标记的影响。本研究的意义在于提供了对组蛋白多腺苷二磷酸核糖基化(S)的表观遗传学机制的新见解(S)，通过该机制可以实现对亚砷酸盐暴露的应激反应基因的转录。这种多聚(ADP-核糖基)的机制可能特别适合于促进高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.