Prolonged FOS activity disrupts a global myogenic transcriptional program by altering 3D chromatin architecture in primary muscle progenitor cells.
Prolonged FOS activity disrupts a global myogenic transcriptional program by altering 3D chromatin architecture in primary muscle progenitor cells.
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长时间的FOS活性通过改变原代肌肉祖细胞中的3D染色质结构来破坏全局的肌原性转录程序。
DOI：
10.1186/s13395-022-00303-x
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发表时间：
2022-08-15
期刊：
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
--
作者：
AP-1转录因子，FBJ骨肉瘤癌基因（FOS），在肌肉损伤后数小时内在成体肌肉卫星细胞（SCs）中被诱导，是有效的干细胞激活和肌肉修复所必需的。然而，为什么在sc作为祖细胞进入细胞周期之前FOS会迅速下调（即瞬时表达），目前尚不清楚。此外，在SCs增殖后代中提高FOS水平是否能增强其成肌特性还需要进一步的研究。我们建立了一个可诱导的FOS表达系统，以评估肌祖细胞体内持续FOS活性的影响。我们进行了各种实验来测量细胞增殖和分化，以及揭示RNA水平和三维（3D）染色质相互作用的变化。原代肌祖细胞中持续的FOS活性严重拮抗其在培养前2周内分化和形成肌管的能力。RNA-seq分析显示，肌祖细胞中的异位FOS活性抑制了全局的促肌转录程序，同时激活了应激诱导的有丝分裂原激活的蛋白激酶（MAPK）转录特征。此外，我们在A/B区室、拓扑相关结构域（TADs）和fos调控基因附近的基因组环中观察到各种fos依赖性的染色体重组事件。我们的研究结果表明，在最近激活的肌肉祖细胞中，FOS活性的升高通过改变关键的促肌基因附近的3D染色体组织来扰乱细胞分化。这项工作强调了在肌肉谱系中严格控制FOS表达的重要性，并表明在慢性应激或疾病状态下，肌肉前体细胞中持续的FOS活性可能会破坏肌肉形成过程。在线版本包含补充材料，可在10.1186/s13395-022-00303-x获得。
The AP-1 transcription factor, FBJ osteosarcoma oncogene (FOS), is induced in adult muscle satellite cells (SCs) within hours following muscle damage and is required for effective stem cell activation and muscle repair. However, why FOS is rapidly downregulated before SCs enter cell cycle as progenitor cells (i.e., transiently expressed) remains unclear. Further, whether boosting FOS levels in the proliferating progeny of SCs can enhance their myogenic properties needs further evaluation. We established an inducible, FOS expression system to evaluate the impact of persistent FOS activity in muscle progenitor cells ex vivo. We performed various assays to measure cellular proliferation and differentiation, as well as uncover changes in RNA levels and three-dimensional (3D) chromatin interactions. Persistent FOS activity in primary muscle progenitor cells severely antagonizes their ability to differentiate and form myotubes within the first 2 weeks in culture. RNA-seq analysis revealed that ectopic FOS activity in muscle progenitor cells suppressed a global pro-myogenic transcriptional program, while activating a stress-induced, mitogen-activated protein kinase (MAPK) transcriptional signature. Additionally, we observed various FOS-dependent, chromosomal re-organization events in A/B compartments, topologically associated domains (TADs), and genomic loops near FOS-regulated genes. Our results suggest that elevated FOS activity in recently activated muscle progenitor cells perturbs cellular differentiation by altering the 3D chromosome organization near critical pro-myogenic genes. This work highlights the crucial importance of tightly controlling FOS expression in the muscle lineage and suggests that in states of chronic stress or disease, persistent FOS activity in muscle precursor cells may disrupt the muscle-forming process. The online version contains supplementary material available at 10.1186/s13395-022-00303-x.
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影响因子：
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