Folate deficiency facilitates recruitment of upstream binding factor to hot spots of DNA double-strand breaks of rRNA genes and promotes its transcription.
Folate deficiency facilitates recruitment of upstream binding factor to hot spots of DNA double-strand breaks of rRNA genes and promotes its transcription.
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叶酸缺乏促进上游结合因子募集到 rRNA 基因 DNA 双链断裂的热点并促进其转录
DOI：
10.1093/nar/gkw1208
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发表时间：
2017-03-17
影响因子：
14.9
通讯作者：
Zhang T
中科院分区：
文献类型：
--
作者：
Xie Q;Li C;Song X;Wu L;Jiang Q;Qiu Z;Cao H;Yu K;Wan C;Li J;Yang F;Huang Z;Niu B;Jiang Z;Zhang T
摘要核糖体在体内的生物合成是细胞功能的重要过程。核糖体RNA（rRNA）基因的转录是受环境条件控制的核糖体生物合成的限速步骤。本文研究了叶酸拮抗剂对小鼠胚胎干细胞DNA双链断裂（DSB）的影响。在这些细胞的基因组中检测到显着的DSB增强，并且这些DSB中的绝大多数存在于rRNA基因中。此外，在叶酸缺乏条件下细胞中的自发DSB仅位于rRNA基因单位内，代表H3K4me1标志。H3K4me1在DSB热点区域的富集增强了上游结合因子（UBF）对rRNA基因的募集，导致rRNA基因转录增加。补充叶酸可恢复rRNA基因DNA断裂位点的UBF结合，并使rRNA基因转录正常。在低叶酸水平的神经管缺陷（NTDs）样本中，观察到rRNA基因转录上调，沿着异常UBF水平。我们的研究结果提出了一个新的观点，叶酸水平的改变影响DNA断裂，通过表观遗传控制导致rRNA基因转录的调节在早期的发展阶段。
Abstract The biogenesis of ribosomes in vivo is an essential process for cellular functions. Transcription of ribosomal RNA (rRNA) genes is the rate-limiting step in ribosome biogenesis controlled by environmental conditions. Here, we investigated the role of folate antagonist on changes of DNA double-strand breaks (DSBs) landscape in mouse embryonic stem cells. A significant DSB enhancement was detected in the genome of these cells and a large majority of these DSBs were found in rRNA genes. Furthermore, spontaneous DSBs in cells under folate deficiency conditions were located exclusively within the rRNA gene units, representing a H3K4me1 hallmark. Enrichment H3K4me1 at the hot spots of DSB regions enhanced the recruitment of upstream binding factor (UBF) to rRNA genes, resulting in the increment of rRNA genes transcription. Supplement of folate resulted in a restored UBF binding across DNA breakage sites of rRNA genes, and normal rRNA gene transcription. In samples from neural tube defects (NTDs) with low folate level, up-regulation of rRNA gene transcription was observed, along with aberrant UBF level. Our results present a new view by which alterations in folate levels affects DNA breakage through epigenetic control leading to the regulation of rRNA gene transcription during the early stage of development.