Variable cardiac α-actin (Actc1) expression in early adult skeletal muscle correlates with promoter methylation

Publication date: Available online 26 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Jordan K. Boutilier, Rhonda L. Taylor, Ramesh Ram, Elyshia McNamara, Quang Nguyen, Hayley Goullee, David Chandler, Munish Mehta, Lois Balmer, Nigel G. Laing, Grant Morahan, Kristen J. Nowak
Different genes encode the a-actin isoforms that are predominantly expressed in heart and muscle. Mutations in the skeletal muscle α-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 α-actin (ACTC1). ACTC1 is the predominant striated α-actin isoform in the heart but is also expressed in developing skeletal muscle. To develop a translatable therapy, we investigated the genetic regulation of Actc1 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 Actc1 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 Actc1 expression. Additionally we interrogated the CC founder haplotype contributions to enable prioritisation of genetic variants for functional analyses. Methylation around the Actc1 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 Actc1 expression in early adult skeletal muscles.Author SummaryMutations in the skeletal muscle actin gene (ACTA1) cause a severe muscle disease that is usually fatal within the first year of life. Some patients with mutations in the ACTA1 gene do not have any ACTA1 protein present in their skeletal muscles. We have previously shown that some of these patients retain expression of the foetal isoform of the gene, cardiac actin (ACTC1). Further, patients who have ACTC1 expressed in their skeletal muscles have increased longevity and improved muscle function, suggesting that upregulation of ACTC1 may be a viable therapy for ACTA1 disease patients. Thus, we have investigated the mechanisms regulating expression of Actc1 in a genetically diverse population of different mouse strains with the aim of identifying the regulatory controls that cause the gene to be switched off. We identified a number of sequence variants present in Actc1 regulatory regions and show that increased promoter methylation is inversely correlated with Actc1 expression. We also show that expression of ACTC1 in humans is likely to be influenced by non-coding sequence variation in regulatory regions upstream and downstream of the gene. Our findings build on previous work and identify regulatory regions of the genome that can now be investigated further.



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