Regenerating zebrafish fin epigenome is characterized by stable lineage-specific DNA methylation and dynamic chromatin accessibility
Regenerating zebrafish fin epigenome is characterized by stable lineage-specific DNA methylation and dynamic chromatin accessibility
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DOI：
10.1186/s13059-020-1948-0
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发表时间：
2020-02-27
期刊：
影响因子：
12.3
通讯作者：
Johnson, Stephen L.
中科院分区：
文献类型：
--
作者：
Lee, Hyung Joo;Hou, Yiran;Johnson, Stephen L.
斑马鱼可以通过形成芽基（blastema）忠实地再生受损的鳍，芽基是一团增殖细胞，可以生长和发育成失去的身体部分。截肢后，各种细胞类型有助于芽基形成，其中每种细胞类型保留命运限制并专门有助于其自身谱系的再生。再生过程中与谱系限制相关的表观遗传变化仍未得到充分研究。结果我们制作了未受伤和再生鳍中成骨细胞和其他细胞的表观基因组图谱，包括DNA甲基化和染色质可及性，以及转录组。这项工作揭示了再生是一个高度动态和协调的转录组和染色质可及性变化的过程，加上稳定维持的谱系特异性DNA甲基化。表观遗传特征还揭示了许多新的再生特异性增强子，这些增强子已经过实验验证。通过对表观基因组图谱的综合分析构建了对再生重要的调控网络，并且预测的上游调控因子的敲除破坏了正常再生，验证了我们的预测。结论在再生过程中，细胞系特异性DNA甲基化特征得以稳定维持，再生促进剂在损伤前被预设为低甲基化。相反，染色质可及性在再生过程中动态变化。许多驱动再生基因表达的增强子以及再生的上游调节子通过整合表观基因组分析被鉴定和验证。
Background Zebrafish can faithfully regenerate injured fins through the formation of a blastema, a mass of proliferative cells that can grow and develop into the lost body part. After amputation, various cell types contribute to blastema formation, where each cell type retains fate restriction and exclusively contributes to regeneration of its own lineage. Epigenetic changes that are associated with lineage restriction during regeneration remain underexplored. Results We produce epigenome maps, including DNA methylation and chromatin accessibility, as well as transcriptomes, of osteoblasts and other cells in uninjured and regenerating fins. This effort reveals regeneration as a process of highly dynamic and orchestrated transcriptomic and chromatin accessibility changes, coupled with stably maintained lineage-specific DNA methylation. The epigenetic signatures also reveal many novel regeneration-specific enhancers, which are experimentally validated. Regulatory networks important for regeneration are constructed through integrative analysis of the epigenome map, and a knockout of a predicted upstream regulator disrupts normal regeneration, validating our prediction. Conclusion Our study shows that lineage-specific DNA methylation signatures are stably maintained during regeneration, and regeneration enhancers are preset as hypomethylated before injury. In contrast, chromatin accessibility is dynamically changed during regeneration. Many enhancers driving regeneration gene expression as well as upstream regulators of regeneration are identified and validated through integrative epigenome analysis.