Comparative genomics analyses reveal sequence determinants underlying interspecies variations in injury-responsive enhancers.
Comparative genomics analyses reveal sequence determinants underlying interspecies variations in injury-responsive enhancers.
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DOI：
10.1186/s12864-023-09283-8
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发表时间：
2023-04-05
期刊：
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
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损伤诱导深刻的转录重塑事件，这可能导致不同物种的伤口愈合，部分组织修复或完全再生。损伤应答增强子（injury responsive enhancers，IREs）是一种顺式调控元件，在某些生物体如斑马鱼和苍蝇中被激活，并被证明能促进组织再生。然而，IREs在哺乳动物中的功能意义仍然难以捉摸。此外，由IREs引起的损伤后的转录反应是否在不同物种中是保守的或特化的，以及IREs的功能变异的基础是什么样的序列特征尚未阐明。我们通过综合表观基因组学和转录组学分析确定了一组在心肌缺血诱导的损伤后再生和非再生新生小鼠心脏中激活的IRE。基序富集分析表明，AP-1和ETS转录因子结合基序显着富集在斑马鱼和小鼠IREs。然而，IRE相关基因在两个物种之间差异很大。我们进一步发现，斑马鱼和小鼠的IRE相关序列差异很大，IRE诱导的缺失伴随着AP-1和ETS基序频率的降低。斑马鱼和小鼠间IRE的功能转换与损伤后IRE相关基因转录反应的变化相关。以小鼠心肌细胞为模型，我们证明了AP-1或ETS基序频率的降低减弱了IRES对缺氧诱导的损伤的反应。通过对IRE进行比较基因组学分析，我们证明了AP-1和ETS基序的物种间变异可能在确定损伤反应过程中增强子的功能方面发挥重要作用。我们的研究结果提供了重要的见解，了解跨物种损伤的转录重塑的分子机制。在线版本包含补充材料，可通过10.1186/s12864-023-09283-8获得。
Injury induces profound transcriptional remodeling events, which could lead to only wound healing, partial tissue repair, or perfect regeneration in different species. Injury-responsive enhancers (IREs) are cis-regulatory elements activated in response to injury signals, and have been demonstrated to promote tissue regeneration in some organisms such as zebrafish and flies. However, the functional significances of IREs in mammals remain elusive. Moreover, whether the transcriptional responses elicited by IREs upon injury are conserved or specialized in different species, and what sequence features may underlie the functional variations of IREs have not been elucidated. We identified a set of IREs that are activated in both regenerative and non-regenerative neonatal mouse hearts upon myocardial ischemia-induced damage by integrative epigenomic and transcriptomic analyses. Motif enrichment analysis showed that AP-1 and ETS transcription factor binding motifs are significantly enriched in both zebrafish and mouse IREs. However, the IRE-associated genes vary considerably between the two species. We further found that the IRE-related sequences in zebrafish and mice diverge greatly, with the loss of IRE inducibility accompanied by a reduction in AP-1 and ETS motif frequencies. The functional turnover of IREs between zebrafish and mice is correlated with changes in transcriptional responses of the IRE-associated genes upon injury. Using mouse cardiomyocytes as a model, we demonstrated that the reduction in AP-1 or ETS motif frequency attenuates the activation of IREs in response to hypoxia-induced damage. By performing comparative genomics analyses on IREs, we demonstrated that inter-species variations in AP-1 and ETS motifs may play an important role in defining the functions of enhancers during injury response. Our findings provide important insights for understanding the molecular mechanisms of transcriptional remodeling in response to injury across species. The online version contains supplementary material available at 10.1186/s12864-023-09283-8.
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影响因子：
11.8
作者：
Goldman JA;Kuzu G;Lee N;Karasik J;Gemberling M;Foglia MJ;Karra R;Dickson AL;Sun F;Tolstorukov MY;Poss KD
通讯作者：
Poss KD
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
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Glass CK
影响因子：
16.6
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Gladka MM;Kohela A;Molenaar B;Versteeg D;Kooijman L;Monshouwer-Kloots J;Kremer V;Vos HR;Huibers MMH;Haigh JJ;Huylebroeck D;Boon RA;Giacca M;van Rooij E
通讯作者：
van Rooij E
影响因子：
64.8
作者：
Kang J;Hu J;Karra R;Dickson AL;Tornini VA;Nachtrab G;Gemberling M;Goldman JA;Black BL;Poss KD
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Poss KD
影响因子：
16.6
作者：
Cui M;Atmanli A;Morales MG;Tan W;Chen K;Xiao X;Xu L;Liu N;Bassel-Duby R;Olson EN
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Olson EN