Effects of Myotonic Dystrophy (DM1) models on hepatocyte transcriptomes
Myotonic Dystrophy (DM1), a common neuromuscular disease, has been shown to have detrimental effects on the livers of patients. To study whether DM1 is directly altering liver function or whether these effects are secondary to DM1 induced functional changes in other tissues, we sequenced the transcriptomes of hepatocytes from liver-specific and whole-body murine models of DM1. We found substantial transcriptomic alteration in the liver-specific model, along with distinguishable physiological changes in the livers of both the liver-specific and whole-body models. This data serves as a survey of transcriptomic alterations in occurring in the livers of DM1 patients. Overall design: A whole-body model for DM1 was developed by Maurice Swanson (Kanadia et al., 2003) by interrupting the expression of Mbnl1, the key splicing factor thought to be responsible for the effects of DM1 in muscle tissue, globally in FVB mice. We isolated hepatocytes from these Mbnl1 KO mice as well as FVB controls and performed hi-resolution bulk RNA-Seq upon them. Additionally, we developed a liver specific model for DM1 by combining a tissue specific murine model for DM1 developed by Thomas Cooper with a liver specific ApoE promoter. This model works by utilizing the ApoE promoter to drive the expression of a reverse tetracycline trans-activator (rtTA), which when exposed to doxycycline (dox) induces the expression of a toxic, trinucleotide (CUG) repeat RNA responsible for causing DM1. By feeding these mice dox in their diet from birth, we can induce DM1 in the liver specifically. Hepatocytes from these mice as well as mice lacking the DM1 inducing allele (but still fed dox) were isolated and RNA-seq was performed upon them.