한빛사 논문
Hyung Joo Lee1,2,*,†, Yiran Hou1,2,†, Yujie Chen1,2, Zea Z. Dailey1,2, Aiyana Riddihough1,2, Hyo Sik Jang1,2, Ting Wang1,2,3,* and Stephen L. Johnson1,‡
1Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA. 2Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. 3McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA.
* Correspondence
†Hyung Joo Lee and Yiran Hou contributed equally to this work.
‡Stephen L. Johnson is deceased. This paper is dedicated to his memory.
Abstract
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.
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