Prolonged FOS activity disrupts a global myogenic transcriptional program by altering 3D chromatin architecture in primary muscle progenitor cells.

IF 5.3 2区医学 Q2 CELL BIOLOGY Skeletal Muscle Pub Date : 2022-08-15 DOI:10.1186/s13395-022-00303-x

A Rasim Barutcu, Gabriel Elizalde, Alfredo E Gonzalez, Kartik Soni, John L Rinn, Amy J Wagers, Albert E Almada

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Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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长时间的 FOS 活性通过改变原生肌肉祖细胞的三维染色质结构，破坏了全局性的成肌转录程序。

背景：AP-1转录因子FBJ骨肉瘤癌基因（FOS）在肌肉损伤后数小时内就会在成肌卫星细胞（SCs）中被诱导，是干细胞有效激活和肌肉修复所必需的。然而，为什么FOS会在SCs作为祖细胞进入细胞周期之前迅速下调（即瞬时表达），目前仍不清楚。此外，提高 SCs 增殖祖细胞中的 FOS 水平是否能增强其致肌特性还需要进一步评估：我们建立了一个可诱导的 FOS 表达系统，以评估 FOS 在体内外肌肉祖细胞中持续活性的影响。我们进行了各种实验来测量细胞的增殖和分化，并揭示了 RNA 水平和三维染色质相互作用的变化：结果：原代肌肉祖细胞中持续存在的 FOS 活性严重影响了它们在培养头两周内分化和形成肌管的能力。RNA-seq分析显示，肌肉祖细胞中异位的FOS活性抑制了全局性的促肌肉生成转录程序，同时激活了应激诱导的丝裂原活化蛋白激酶（MAPK）转录特征。此外，我们还观察到 FOS 调控基因附近的 A/B 区、拓扑相关域（TAD）和基因组环路中发生了各种依赖 FOS 的染色体重组事件：我们的研究结果表明，最近激活的肌肉祖细胞中升高的 FOS 活性会通过改变关键的促肌肉生成基因附近的三维染色体组织来扰乱细胞分化。这项工作强调了严格控制 FOS 在肌肉系中表达的重要性，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。

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来源期刊

Skeletal Muscle CELL BIOLOGY-

CiteScore

9.10

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.