Genome-Wide Profiling of PARP1 Reveals an Interplay with Gene Regulatory Regions and DNA Methylation.
Genome-Wide Profiling of PARP1 Reveals an Interplay with Gene Regulatory Regions and DNA Methylation.
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DOI：
10.1371/journal.pone.0135410
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Fondufe-Mittendorf YN
中科院分区：
文献类型：
--
作者：
Nalabothula N;Al-jumaily T;Eteleeb AM;Flight RM;Xiaorong S;Moseley H;Rouchka EC;Fondufe-Mittendorf YN
聚（adp -核糖）聚合酶-1 （PARP1）是一种参与DNA修复、染色质重塑和基因表达的核酶。PARP1与染色质结构多蛋白复合物（即核小体）的相互作用改变了染色质结构，导致基因表达的变化。染色质结构影响基因调控过程，包括转录、剪接、DNA修复、复制和重组。重要的是要确定PARP1是随机与核小体结合，还是存在于整个细胞基因组的特定核小体区域。为了解决这些问题，我们在乳腺癌细胞系中进行了全基因组关联研究。我们的研究表明，PARP1与全基因组的表观遗传调控元件相关，如活性组蛋白标记、CTCF和dna酶敏感位点。此外，PARP1与全基因组染色质的结合与DNA甲基化模式是互斥的，这表明PARP1与DNA甲基化之间存在功能上的相互作用。事实上，抑制PARylation会导致DNA甲基化模式的全基因组变化。我们的研究结果表明，PARP1控制基因转录的保真度，并通过选择性结合转录活性染色质标记活跃转录的基因区域。这些研究为我们理解PARP1在基因调控中的作用提供了一个平台。
Poly (ADP-ribose) polymerase-1 (PARP1) is a nuclear enzyme involved in DNA repair, chromatin remodeling and gene expression. PARP1 interactions with chromatin architectural multi-protein complexes (i.e. nucleosomes) alter chromatin structure resulting in changes in gene expression. Chromatin structure impacts gene regulatory processes including transcription, splicing, DNA repair, replication and recombination. It is important to delineate whether PARP1 randomly associates with nucleosomes or is present at specific nucleosome regions throughout the cell genome. We performed genome-wide association studies in breast cancer cell lines to address these questions. Our studies show that PARP1 associates with epigenetic regulatory elements genome-wide, such as active histone marks, CTCF and DNase hypersensitive sites. Additionally, the binding of PARP1 to chromatin genome-wide is mutually exclusive with DNA methylation pattern suggesting a functional interplay between PARP1 and DNA methylation. Indeed, inhibition of PARylation results in genome-wide changes in DNA methylation patterns. Our results suggest that PARP1 controls the fidelity of gene transcription and marks actively transcribed gene regions by selectively binding to transcriptionally active chromatin. These studies provide a platform for developing our understanding of PARP1’s role in gene regulation.