Hamed Munerah, Khilji Saadia, Dixon Katherine, Blais Alexandre, Ioshikhes Ilya, Chen Jihong, Li Qiao
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Nucleic Acids Res. 2017 Nov 2;45(19):11236-11248. doi: 10.1093/nar/gkx800.
While skeletal myogenesis is tightly coordinated by myogenic regulatory factors including MyoD and myogenin, chromatin modifications have emerged as vital mechanisms of myogenic regulation. We have previously established that bexarotene, a clinically approved agonist of retinoid X receptor (RXR), promotes the specification and differentiation of skeletal muscle lineage. Here, we examine the genome-wide impact of rexinoids on myogenic differentiation through integral RNA-seq and ChIP-seq analyses. We found that bexarotene promotes myoblast differentiation through the coordination of exit from the cell cycle and the activation of muscle-related genes. We uncovered a new mechanism of rexinoid action which is mediated by the nuclear receptor and largely reconciled through a direct regulation of MyoD gene expression. In addition, we determined a rexinoid-responsive residue-specific histone acetylation at a distinct chromatin state associated to MyoD and myogenin. Thus, we provide novel molecular insights into the interplay between RXR signaling and chromatin states pertinent to myogenic programs in early myoblast differentiation.
虽然骨骼肌生成由包括MyoD和肌细胞生成素在内的肌源性调节因子紧密协调，但染色质修饰已成为肌源性调节的重要机制。我们之前已经确定，贝沙罗汀是一种临床批准的视黄酸X受体（RXR）激动剂，可促进骨骼肌谱系的特化和分化。在这里，我们通过整合RNA测序和ChIP测序分析，研究了视黄酸类药物对肌源性分化的全基因组影响。我们发现，贝沙罗汀通过协调细胞周期退出和肌肉相关基因的激活来促进成肌细胞分化。我们揭示了一种新的视黄酸类药物作用机制，该机制由核受体介导，并且在很大程度上通过对MyoD基因表达的直接调节来协调。此外，我们在与MyoD和肌细胞生成素相关的独特染色质状态下确定了视黄酸类药物反应性残基特异性组蛋白乙酰化。因此，我们为RXR信号与早期成肌细胞分化中与肌源性程序相关的染色质状态之间的相互作用提供了新的分子见解。
