Resolving Heart Regeneration by Replacement Histone Profiling.
Resolving Heart Regeneration by Replacement Histone Profiling.
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DOI：
10.1016/j.devcel.2017.01.013
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发表时间：
2017-02-27
影响因子：
11.8
通讯作者：
Poss KD
中科院分区：
文献类型：
--
作者：
Goldman JA;Kuzu G;Lee N;Karasik J;Gemberling M;Foglia MJ;Karra R;Dickson AL;Sun F;Tolstorukov MY;Poss KD
染色质调节是动物发育的主要机制，但目前尚不清楚染色质结构变化在多大程度上是组织再生的基础。非哺乳类脊椎动物，如斑马鱼，在组织损伤后激活心肌细胞（CM）分裂，以再生失去的心肌。在这里，我们产生了转基因斑马鱼表达生物素化的H3.3组蛋白变异体的CM和衍生细胞类型特异性的组蛋白替代配置文件。我们确定了一个新兴的程序推定的增强子，修改H3.3占用再生过程中，覆盖在全基因组范围内减少H3.3从启动子。在转基因报告细胞系中，富含H3.3的元件指导CM亚群中的基因表达。其他元素增加了H3.3富集，并在损伤和/或Neuregulin 1引起的CM增殖的情况下显示增强子活性。数十个含有预测的转录因子结合位点的共有序列基序富集在具有再生响应性H3.3占用的基因组区域中。因此，组织再生的细胞类型特异性调控程序可以通过全基因组H3.3谱来揭示。细胞类型特异性染色质分析可以揭示内在遗传程序，但再生组织中的这种分析具有技术挑战。Goldman，Kuzu等人开发了转基因斑马鱼，使心肌细胞特异性组蛋白H3.3谱能够捕获核小体转换的位点。他们确定了在动态过程中优先用于心脏再生的调节元件。
Chromatin regulation is a principal mechanism governing animal development, yet it is unclear to what extent structural changes in chromatin underlie tissue regeneration. Non-mammalian vertebrates like zebrafish activate cardiomyocyte (CM) division after tissue damage to regenerate lost heart muscle. Here, we generated transgenic zebrafish expressing a biotinylatable H3.3 histone variant in CMs and derived cell type-specific profiles of histone replacement. We identified an emerging program of putative enhancers that revise H3.3 occupancy during regeneration, overlaid upon a genome-wide reduction of H3.3 from promoters. In transgenic reporter lines, H3.3-enriched elements directed gene expression in subpopulations of CMs. Other elements increased H3.3 enrichment and displayed enhancer activity in settings of injury- and/or Neuregulin1-elicited CM proliferation. Dozens of consensus sequence motifs containing predicted transcription factor binding sites were enriched in genomic regions with regeneration-responsive H3.3 occupancy. Thus, cell-type specific regulatory programs of tissue regeneration can be revealed by genome-wide H3.3 profiling. Cell type-specific chromatin profiling can shed light on intrinsic genetic programs but such analysis in regenerating tissues has technical challenges. Goldman, Kuzu et al. develop transgenic zebrafish enabling cardiomyocyte-specific histone H3.3 profiling to capture sites of nucleosome turnover. They identify regulatory elements preferential for heart regeneration during the dynamic process.