Dynamic enhancers control skeletal muscle identity and reprogramming
Dynamic enhancers control skeletal muscle identity and reprogramming
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动态增强剂控制骨骼肌的身份和重编程
作者：
Krithika Ramachandran;Madhavi D. Senagolage;Meredith A. Sommars;C. Futtner;Yasuhiro Omura;Amanda L. Allred;G. Barish
骨骼肌由具有不同代谢活性和收缩性的纤维组成，这些纤维在长期运动中被重塑，但肌肉特性和适应性的表观基因组基础仍然知之甚少。在这里，我们使用染色质免疫沉淀测序的二甲基化组蛋白3赖氨酸4和乙酰化组蛋白3赖氨酸27，以及转座酶可访问的染色质分析，解剖跨肌肉群的顺式调控网络。我们证明，在体内增强指定肌肉根据肌纤维组成，显示培养的肌管增强剂的相似性不大，并确定糖酵解和氧化肌肉特异性调节剂。此外，我们发现自愿轮运行和肌肉特异性过氧化物酶体增殖物激活受体γ共激活因子-1 α（Pgc 1a）转基因（mTg）过表达，刺激小鼠的耐力表现，导致表观基因组的显着不同的变化。运动主要导致增强子hypoacetylation，而mTg导致在不同的网站hyperacetylation。调控区域和基因表达的综合分析显示，运动和mTg分别与肌细胞增强因子（MEF）2和雌激素相关受体（ERR）信号传导和促进氧化代谢的基因转录相关。然而，运动还与类维生素A X受体（RXR）、jun原癌基因（JUN）、正弦眼同源盒因子（SIX）和其他因素的调节有关。总的来说，我们的工作定义了体内骨骼肌独特的增强子库，并揭示了不同的运动诱导或PGC 1 α驱动的表观基因组程序指导部分收敛的转录网络。
Skeletal muscles consist of fibers of differing metabolic activities and contractility, which become remodeled in response to chronic exercise, but the epigenomic basis for muscle identity and adaptation remains poorly understood. Here, we used chromatin immunoprecipitation sequencing of dimethylated histone 3 lysine 4 and acetylated histone 3 lysine 27 as well as transposase-accessible chromatin profiling to dissect cis-regulatory networks across muscle groups. We demonstrate that in vivo enhancers specify muscles in accordance with myofiber composition, show little resemblance to cultured myotube enhancers, and identify glycolytic and oxidative muscle-specific regulators. Moreover, we find that voluntary wheel running and muscle-specific peroxisome proliferator–activated receptor gamma coactivator-1 alpha (Pgc1a) transgenic (mTg) overexpression, which stimulate endurance performance in mice, result in markedly different changes to the epigenome. Exercise predominantly leads to enhancer hypoacetylation, whereas mTg causes hyperacetylation at different sites. Integrative analysis of regulatory regions and gene expression revealed that exercise and mTg are each associated with myocyte enhancer factor (MEF) 2 and estrogen-related receptor (ERR) signaling and transcription of genes promoting oxidative metabolism. However, exercise was additionally associated with regulation by retinoid X receptor (RXR), jun proto-oncogene (JUN), sine oculis homeobox factor (SIX), and other factors. Overall, our work defines the unique enhancer repertoires of skeletal muscles in vivo and reveals that divergent exercise-induced or PGC1α-driven epigenomic programs direct partially convergent transcriptional networks.
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影响因子：
29
作者：
Zechner C;Lai L;Zechner JF;Geng T;Yan Z;Rumsey JW;Collia D;Chen Z;Wozniak DF;Leone TC;Kelly DP
通讯作者：
Kelly DP
影响因子：
29
作者：
Da Cruz S;Parone PA;Lopes VS;Lillo C;McAlonis-Downes M;Lee SK;Vetto AP;Petrosyan S;Marsala M;Murphy AN;Williams DS;Spiegelman BM;Cleveland DW
通讯作者：
Cleveland DW
DOI：
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发表时间：
2007
影响因子：
11.1
作者：
S. Jäger;C. Handschin;J. St-Pierre;B. Spiegelman
通讯作者：
S. Jäger;C. Handschin;J. St-Pierre;B. Spiegelman
影响因子：
8.8
作者：
Fan W;He N;Lin CS;Wei Z;Hah N;Waizenegger W;He MX;Liddle C;Yu RT;Atkins AR;Downes M;Evans RM
通讯作者：
Evans RM
影响因子：
8.8
作者：
Baek S;Goldstein I;Hager GL
通讯作者：
Hager GL