雄性小鼠骨骼肌萎缩期间顺式调节网络的重编程,Nature Communications

顺式调控元件及其动态活性的综合图谱对于了解细胞结构维持、代谢和对环境的反应的转录基础是必要的。在这里，我们使用来自幼年雄性C57BL6小鼠的匹配单核染色质可及性和 RNA 测序，展示了正常和去神经骨骼肌中可及染色质区域的图谱。我们确定了细胞类型特异性的顺式调节网络，强调了介导肌核类型之间转变的动态调节回路。通过比较正常和受干扰的肌肉，我们描述了顺式调节网络响应去神经支配的重新编程，描述了启动子/增强子和靶基因的相互作用。我们进一步揭示了转录因子的层次结构，描绘了萎缩肌肉中的调节网络，将 ELK4 确定为与萎缩相关的关键转录因子，通过 TGF-β1 调节引发肌肉萎缩。这项研究提供了丰富的基因组资源，对于解码生理和病理状态下骨骼肌的调节动力学至关重要。

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A comprehensive atlas of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of cellular structure maintenance, metabolism, and responses to the environment. Here we show, using matched single-nucleus chromatin accessibility and RNA-sequencing from juvenile male C57BL6 mice, an atlas of accessible chromatin regions in both normal and denervated skeletal muscles. We identified cell-type-specific cis-regulatory networks, highlighting the dynamic regulatory circuits mediating transitions between myonuclear types. Through comparison of normal and perturbed muscle, we delineated the reprogramming of cis-regulatory networks in response to denervation, described the interplay of promoters/enhancers and target genes. We further unveil a hierarchical structure of transcription factors that delineate a regulatory network in atrophic muscle, identifying ELK4 as a key atrophy-related transcription factor that instigates muscle atrophy through TGF-β1 regulation. This study furnishes a rich genomic resource, essential for decoding the regulatory dynamics of skeletal muscle in both physiological and pathological states.