A Novel Epigenetic Silencing Pathway Involving the Highly Conserved 5'-3' Exoribonuclease Dhp1/Rat1/Xrn2 in Schizosaccharomyces pombe.
A Novel Epigenetic Silencing Pathway Involving the Highly Conserved 5'-3' Exoribonuclease Dhp1/Rat1/Xrn2 in Schizosaccharomyces pombe.
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DOI：
10.1371/journal.pgen.1005873
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发表时间：
2016-02
期刊：
影响因子：
4.5
通讯作者：
Zhang K
中科院分区：
文献类型：
--
作者：
Tucker JF;Ohle C;Schermann G;Bendrin K;Zhang W;Fischer T;Zhang K
表观遗传基因沉默在调控基因表达中起着至关重要的作用，并有助于真核生物的有机体发育和细胞命运获得。在分裂酵母、裂糖酵母中，已知异染色质相关基因沉默是由RNA加工途径介导的，包括RNA干扰（RNAi）和3 ‘ -5 ’外核糖核酸酶复合物（外泌体）。在这里，我们报道了一种新的rna加工途径，该途径有助于5 ‘ -3 ’外核糖核酸酶Dhp1/Rat1/Xrn2介导的表观遗传基因沉默和异染色质组装。Dhp1突变在着丝粒周围区域和沉默交配型位点引起缺陷性基因沉默。有趣的是，两种dhp1相互作用蛋白（Din1焦磷酸水解酶或Rhn1转录终止因子）的突变都不会导致主要异染色质区域的沉默缺陷。我们证明Dhp1与异色因子相互作用，并且在以独立于RNAi和外泌体的方式建立沉默的顺序步骤中是必不可少的。基因组和遗传分析表明，Dhp1通过其RNA加工活性参与了重复区域的转录后沉默。这些结果描述了Dhp1/Rat1/Xrn2在染色质沉默中的意外作用，并阐明了各种rna加工途径如何共同或单独作用于真核生物基因组的表观遗传调控。表观遗传机制调节生物体何时、何地以及如何使用其基因组中存储的遗传信息。它们对许多细胞过程至关重要，如基因表达调节、基因组组织和细胞命运决定。它们也支配着生长、发展，最终支配着人类健康。异染色质构成沉默的色域，其中基因沉默通过表观遗传机制发生。众所周知，RNA加工途径，如RNA干扰（RNAi）和外泌体，可以通过降解不需要的或异常的转录物来介导基因沉默。在这项研究中，我们描述了一种新的RNA加工机制在表观遗传沉默使用裂变酵母，研究这些过程的首要模型。通过遗传学、细胞生物学和基因组学方法，我们发现了Dhp1的一个以前未被认识到的功能，Dhp1是一个高度保守的5 ‘ -3 ’外核糖核酸酶，是出芽酵母Rat1和后生动物Xrn2的同源物。我们发现Dhp1在表观遗传沉默中介导一种新的RNA加工机制，该机制独立于RNAi和外泌体发生。我们的研究结果阐明了多种RNA加工途径如何参与真核基因表达和染色质组织的调节。
Epigenetic gene silencing plays a critical role in regulating gene expression and contributes to organismal development and cell fate acquisition in eukaryotes. In fission yeast, Schizosaccharomyces pombe, heterochromatin-associated gene silencing is known to be mediated by RNA processing pathways including RNA interference (RNAi) and a 3’-5’ exoribonuclease complex, the exosome. Here, we report a new RNA-processing pathway that contributes to epigenetic gene silencing and assembly of heterochromatin mediated by 5’-3’ exoribonuclease Dhp1/Rat1/Xrn2. Dhp1 mutation causes defective gene silencing both at peri-centromeric regions and at the silent mating type locus. Intriguingly, mutation in either of the two well-characterized Dhp1-interacting proteins, the Din1 pyrophosphohydrolase or the Rhn1 transcription termination factor, does not result in silencing defects at the main heterochromatic regions. We demonstrate that Dhp1 interacts with heterochromatic factors and is essential in the sequential steps of establishing silencing in a manner independent of both RNAi and the exosome. Genomic and genetic analyses suggest that Dhp1 is involved in post-transcriptional silencing of repetitive regions through its RNA processing activity. The results describe the unexpected role of Dhp1/Rat1/Xrn2 in chromatin-based silencing and elucidate how various RNA-processing pathways, acting together or independently, contribute to epigenetic regulation of the eukaryotic genome. Epigenetic mechanisms regulate when, where, and how an organism uses the genetic information stored in its genome. They are essential to many cellular processes, such as the regulation of gene expression, genome organization, and cell-fate determination. They also govern growth, development, and ultimately human health. Heterochromatin constitutes silenced chromatic domains, in which gene silencing occurs through epigenetic mechanisms. RNA processing pathways, such as RNA interference (RNAi) and the exosome, are known to mediate the silencing of genes via degradation of unwanted or aberrant transcripts. In this study, we describe a new RNA processing mechanism in epigenetic silencing using fission yeast, a premier model for studying these processes. With genetic, cell biology, and genomic approaches, we uncovered a previously unrecognized function of Dhp1, a highly conserved 5’-3’ exoribonuclease and ortholog of budding yeast Rat1 and metazoan Xrn2. We show that Dhp1 mediates a novel RNA processing mechanism in epigenetic silencing which occurs independently of both RNAi and the exosome. Our results clarify how multiple RNA processing pathways are involved in the regulation of eukaryotic gene expression and chromatin organization.