Understanding the role of DUX4 in FSHD pathology and its connection to early human development
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Understanding the role of DUX4 in FSHD pathology and its connection to early human development


Facioscapulohumeral muscular dystrophy (FSHD) is a rare genetic disease and is considered one of the most prominent muscular dystrophies in human. The disease typically begins with weakening of muscles starting from the upper body (face, shoulders, arms) that eventually spread to the lower body (legs). FSHD patients’ symptoms generally appear at around adolescent and continue to worsen overtime. Currently there is no cure for FSHD; however, clinical management is available to slow down the progression of muscle loss. With the recent advancement in genetic research technology, major mutations that cause the disease were discovered. Most FSHD patients (95%) have a contraction of the D4Z4 repeat macrosatellite at the subtelomeric region of chromosome 4q with a specific haplotype (4qA). These patients are designated as FSHD1. Around 5% of FSHD cases acquire other mutations that disrupt the heterochromatic establishment of D4Z4 repeats such as DNA methylation (termed FSHD2). Their mutations so far were found in the epigenetic modifier genes (SMCHD1, LRIF1, DNMT3B) which might be involved in D4Z4 heterochromatin. DUX4, a transcription factor, is encoded in the D4Z4 repeats. It was found to be re-activated from the last D4Z4 repeat in FSHD patients and has been linked to the development of the disease. During my time in the Yokomori lab, I have characterized FSHD mutant myocytes which were generated by Dr. Xiangduo Kong by CRISPR-Cas9 from a healthy permissive myoblast line. The mutants carry either deletion of D4Z4 repeats or SMCHD1 homozygous mutations or both. I discovered that the mutant cells shared significant characteristics with FSHD patient cells by having a de-repression/reactivation of DUX4. DUX4 was undetected in my RNA-seq analysis but still sufficient to activate FSHD signature genes in FSHD mutants while the parental wildtype cell line had minimal to zero expression of such genes. DUX4 is a double homeobox protein and is involved in embryonic genome activation (EGA). Homeobox family transcription factors are considered to be central in governing early mammalian development. I further characterized DUX4 major downstream targets such as H3.X/Y, LEUTX, and DUXA and demonstrated that they enhance the DUX4 network through positive feedback loop. I also identified a set of embryonic genes that were induced by LEUTX overexpression in FSHD mutant myocytes. Particularly, some of these genes (DPRX, DPPA3) were previously found to be upregulated at 8-cell stage of embryonic development corresponding to LEUTX timing of expression from 4-cell to 8-cell stage. Altogether, these findings suggested that misexpression of LEUTX in FSHD muscles could disrupt muscle differentiation by activation of embryonic genes.

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