Long-range phasing of dynamic, tissue-specific and allele-specific regulatory elements.
Long-range phasing of dynamic, tissue-specific and allele-specific regulatory elements.
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DOI：
10.1038/s41588-022-01188-8
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发表时间：
2022-10
期刊：
影响因子：
30.8
通讯作者：
Bernstein, Bradley E.
中科院分区：
文献类型：
--
作者：
Battaglia, Sofia;Dong, Kevin;Wu, Jingyi;Chen, Zeyu;Najm, Fadi J.;Zhang, Yuanyuan;Moore, Molly M.;Hecht, Vivian;Shoresh, Noam;Bernstein, Bradley E.
表观基因组图谱通过染色质状态鉴定基因调控元件。然而，目前流行的短读测序方法不能有效地区分等位基因，评估基因座中元素的相互依赖性，或捕获单分子动力学。在这里，我们应用靶向纳米孔测序来分析染色质可及性和DNA甲基化的连续~100 kb DNA分子，这些分子跨越了与发育、免疫和印迹相关的位点。我们基于外源性GpC甲基化检测单个分子上的启动子、增强子、绝缘子和转录因子足迹。我们推断了免疫位点内动态元素之间的关系，并在t细胞刺激期间对连续的重塑事件进行了排序。最后，我们对H19/IGF2位点的初级序列和调控元件进行了相位分析，揭示了灵长类动物的特异性特征。其中包括稳定印迹控制区的片段重复和在特定环境下驱动双等位基因IGF2表达的非规范增强子。我们的研究推进了阶段性基因调控景观的新兴策略，并揭示了人类细胞中覆盖IGF2印迹的机制。
Epigenomic maps identify gene regulatory elements by their chromatin state. However, prevailing short-read sequencing methods cannot effectively distinguish alleles, evaluate the inter-dependence of elements in a locus, or capture single-molecule dynamics. Here we apply targeted nanopore sequencing to profile chromatin accessibility and DNA methylation on contiguous ~100-kb DNA molecules that span loci relevant to development, immunity and imprinting. We detect promoters, enhancers, insulators and transcription factor footprints on single molecules based on exogenous GpC methylation. We infer relationships among dynamic elements within immune loci, and order successive remodeling events during T-cell stimulation. Finally, we phase primary sequence and regulatory elements across the H19/IGF2 locus, uncovering primate-specific features. These include a segmental duplication that stabilizes the imprinting control region and a non-canonical enhancer that drives bi-allelic IGF2 expression in specific contexts. Our study advances emerging strategies for phasing gene regulatory landscapes and reveals a mechanism that overrides IGF2 imprinting in human cells.
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影响因子：
3.5
作者：
Freschi A;Del Prete R;Pignata L;Cecere F;Manfrevola F;Mattia M;Cobellis G;Sparago A;Bartolomei MS;Riccio A;Cerrato F
通讯作者：
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64.5
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通讯作者：
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