一个快速肌球蛋白超级增强子通过与肌球蛋白基因的竞争相互作用决定肌肉纤维表型。

A fast Myosin super enhancer dictates muscle fiber phenotype through competitive interactions with Myosin genes.

机构信息

Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France.

Univ Paris Est Creteil, INSERM, EnvA, EFS, AP-HP, IMRB, 94010, Creteil, France.

出版信息

Nat Commun. 2022 Feb 24;13(1):1039. doi: 10.1038/s41467-022-28666-1.

The contractile properties of adult myofibers are shaped by their Myosin heavy chain isoform content. Here, we identify by snATAC-seq a 42 kb super-enhancer at the locus regrouping the fast Myosin genes. By 4C-seq we show that active fast Myosin promoters interact with this super-enhancer by DNA looping, leading to the activation of a single promoter per nucleus. A rainbow mouse transgenic model of the locus including the super-enhancer recapitulates the endogenous spatio-temporal expression of adult fast Myosin genes. In situ deletion of the super-enhancer by CRISPR/Cas9 editing demonstrates its major role in the control of associated fast Myosin genes, and deletion of two fast Myosin genes at the locus reveals an active competition of the promoters for the shared super-enhancer. Last, by disrupting the organization of fast Myosin, we uncover positional heterogeneity within limb skeletal muscles that may underlie selective muscle susceptibility to damage in certain myopathies.

成肌细胞的收缩特性受肌球蛋白重链同工型含量的影响。在这里，我们通过 snATAC-seq 在快速肌球蛋白基因所在的区域鉴定出一个 42kb 的超级增强子。通过 4C-seq，我们表明活跃的快速肌球蛋白启动子通过 DNA 环化与这个超级增强子相互作用，导致每个核中仅激活一个启动子。超级增强子包含在一个包含该基因座的 Rainbow 小鼠转基因模型中，重现了成人快速肌球蛋白基因的内源性时空表达。通过 CRISPR/Cas9 编辑在原位删除超级增强子证明了它在控制相关快速肌球蛋白基因中的主要作用，并且在该基因座上删除两个快速肌球蛋白基因揭示了启动子对共享超级增强子的积极竞争。最后，通过破坏快速肌球蛋白的组织，我们揭示了肢体骨骼肌中的位置异质性，这可能是某些肌病中肌肉对损伤的选择性易感性的基础。