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首页> 外文期刊>Biochimica et Biophysica Acta. Gene Regulatory Mechanisms >Variable cardiac alpha-actin (Actc1) expression in early adult skeletal muscle correlates with promoter methylation
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Variable cardiac alpha-actin (Actc1) expression in early adult skeletal muscle correlates with promoter methylation

机译：可变心脏α-肌动蛋白（ACTC1）早期成人骨骼肌表达与启动子甲基化相关

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Different genes encode the alpha-actin isoforms that are predominantly expressed in heart and skeletal muscle. Mutations in the skeletal muscle alpha-actin gene (ACTA1) cause muscle diseases that are mostly lethal in the early postnatal period. We previously demonstrated that the disease phenotype of ACTA1 mouse models could be rescued by transgenic over-expression of cardiac alpha-actin (ACTC1). ACTC1 is the predominant striated a-actin isoform in the heart but is also expressed in developing skeletal muscle. To develop a translatable therapy, we investigated the genetic regulation of Actcl expression. Using strains from The Collaborative Cross (CC) genetic resource, we found that Actc1 varies in expression by up to 24-fold in skeletal muscle. We defined significant expression quantitative trait loci (eQTL) associated with early adult Actc1 expression in soleus and heart. eQTL in both heart and soleus mapped to the Actc1 locus and replicate an eQTL mapped for Actcl in BXD heart and quadriceps. We built on this previous work by analysing genes within the eQTL peak regions to prioritise likely candidates for modifying Actcl expression. Additionally we interrogated the CC founder haplotype contributions to enable prioritisation of genetic variants for functional analyses. Methylation around the Actcl transcriptional start site in early adult skeletal muscle negatively correlated with Actc1 expression in a strain-dependent manner, while other marks of regulatory potential (histone modification and chromatin accessibility) were unaltered. This study provides novel insights into the complex genetic regulation of Actcl expression in early adult skeletal muscles.
机译：不同的基因编码主要在心脏和骨骼肌中主要表达的α-肌动蛋白同种型。骨骼肌α-肌动蛋白基因（Acta1）的突变导致肌肉疾病在初期的后期大多是致命的。我们之前证明，Acta1小鼠模型的疾病表型可以通过Cartciach-Actin（Actc1）的转基因过表达来拯救。 Actc1是心脏中主要的条纹A-肌动蛋白同种型，但也在发育骨骼肌中表达。为了开发可翻译的疗法，我们研究了Actcl表达的遗传调节。使用来自协同交叉（CC）遗传资源的菌株，我们发现Actc1在表达中变化高达24倍的骨骼肌。我们定义了与Soleus和Heart中的早期成人Actc1表达相关的显着表达量化性状基因座（EQTL）。 EQTL在心脏和索勒斯映射到ACTC1基因座，并复制BXD心脏和Quadriceps的Actcl映射的EQTL。我们通过分析EQTL峰值区域内的基因来构建先前的工作，以优先考虑用于修改Actcl表达的候选人。此外，我们询问了CC创始人单倍型的贡献，以实现遗传变体的优先级，用于功能分析。 actCL转录开始部位的甲基化在早期成年骨骼肌中与应变依赖性方式的ACTC1表达呈负相关，而不妨碍调节潜力的其他标记（组蛋白修饰和染色质）。本研究为早期成人骨骼肌中Actcl表达复杂的遗传调节提供了新的洞察。

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