Journal
BIOMEDICINES
Volume 11, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/biomedicines11072082
Keywords
DMD; dystrophin; gene expression; transcription; mRNA; RNAseq
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This manuscript discusses the challenges in quantifying dystrophin gene expression and presents a transcriptional model to explain the coupling of long transcription time with short mature mRNA half-life. The effects of this model on cellular transcriptional dynamics are explored, and key implications for the study of dystrophin gene expression, focusing on both conventional (qPCR) and next-gen (RNAseq) approaches, are discussed.
At 2.3 megabases in length, the dystrophin gene is enormous: transcription of a single mRNA requires approximately 16 h. Principally expressed in skeletal muscle, the dystrophin protein product protects the muscle sarcolemma against contraction-induced injury, and dystrophin deficiency results in the fatal muscle-wasting disease, Duchenne muscular dystrophy. This gene is thus of key clinical interest, and therapeutic strategies aimed at eliciting dystrophin restoration require quantitative analysis of its expression. Approaches for quantifying dystrophin at the protein level are well-established, however study at the mRNA level warrants closer scrutiny: measured expression values differ in a sequence-dependent fashion, with significant consequences for data interpretation. In this manuscript, we discuss these nuances of expression and present evidence to support a transcriptional model whereby the long transcription time is coupled to a short mature mRNA half-life, with dystrophin transcripts being predominantly nascent as a consequence. We explore the effects of such a model on cellular transcriptional dynamics and then discuss key implications for the study of dystrophin gene expression, focusing on both conventional (qPCR) and next-gen (RNAseq) approaches.
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