The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration.
The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration.
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DOI：
10.1101/gad.234419.113
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发表时间：
2014-03-01
影响因子：
10.5
通讯作者：
Dutta A
中科院分区：
文献类型：
--
作者：
Dey BK;Pfeifer K;Dutta A
H19 长非编码 RNA 在出生后受到抑制，骨骼肌除外。戴伊等人。发现H19外显子1编码miR-675-3p和miR-675-5p。 miR-675-3p 和 miR-675-5p 的表达可以挽救 H19 缺失对肌生成的抑制。通过重新引入 miR-675-3p 和 miR-675-5p 可以纠正 H19 缺陷小鼠中异常的骨骼肌再生。这些 miR 靶向抗分化 Smad 转录因子和 DNA 复制起始因子 Cdc6。总之，H19 产生 microRNA 来促进骨骼肌分化和再生。 H19 长非编码 RNA 基因的调控表达已被充分表征为基因组印记的范例，但 H19 RNA 的生物学功能仍不清楚。 H19 在胚胎组织中在母体中大量表达，但在出生后受到强烈抑制，并且显着的转录仅在骨骼肌中持续存在。因此，我们研究了 H19 RNA 在骨骼肌分化和再生中的作用。成肌细胞和 H19 敲除小鼠卫星细胞中 H19 RNA 的敲低会降低分化。 H19 外显子 1 编码两个保守的 microRNA，即 miR-675-3p 和 miR-675-5p，这两者均在骨骼肌分化过程中被诱导。成肌细胞分化过程中 H19 缺失对肌生成的抑制可通过 miR-675-3p 和 miR-675-5p 的外源表达来挽救。 H19 缺陷小鼠在损伤后表现出异常的骨骼肌再生，可通过重新引入 miR-675-3p 和 miR-675-5p 来纠正。 miR-675-3p 和 miR-675-5p 通过直接靶向和下调对骨形态发生蛋白 (BMP) 途径至关重要的抗分化 Smad 转录因子和 DNA 复制起始因子 Cdc6 发挥作用。因此，H19长非编码RNA在骨骼肌分化和再生中具有关键的反式调节功能，该功能是由H19内编码的microRNA介导的。
The H19 long noncoding RNA is repressed after birth, except in skeletal muscle. Dey et al. discover that H19 exon1 encodes miR-675-3p and miR-675-5p. The inhibition of myogenesis by H19 depletion is rescued by expression of miR-675-3p and miR-675-5p. The abnormal skeletal muscle regeneration in H19-deficient mice is rectified by reintroducing miR-675-3p and miR-675-5p. These miRs target the anti-differentiation Smad transcription factors and the DNA replication initiation factor Cdc6. In summary, H19 gives rise to microRNAs to promote skeletal muscle differentiation and regeneration. Regulated expression of the H19 long noncoding RNA gene has been well characterized as a paradigm for genomic imprinting, but the H19 RNA's biological function remains largely unclear. H19 is abundantly expressed maternally in embryonic tissues but is strongly repressed after birth, and significant transcription persists only in skeletal muscle. Thus, we examined the role of the H19 RNA in skeletal muscle differentiation and regeneration. Knockdown of H19 RNA in myoblast cells and H19 knockout mouse satellite cells decreases differentiation. H19 exon1 encodes two conserved microRNAs, miR-675-3p and miR-675-5p, both of which are induced during skeletal muscle differentiation. The inhibition of myogenesis by H19 depletion during myoblast differentiation is rescued by exogenous expression of miR-675-3p and miR-675-5p. H19-deficient mice display abnormal skeletal muscle regeneration after injury, which is rectified by reintroduction of miR-675-3p and miR-675-5p. miR-675-3p and miR-675-5p function by directly targeting and down-regulating the anti-differentiation Smad transcription factors critical for the bone morphogenetic protein (BMP) pathway and the DNA replication initiation factor Cdc6. Therefore, the H19 long noncoding RNA has a critical trans-regulatory function in skeletal muscle differentiation and regeneration that is mediated by the microRNAs encoded within H19.