15 Mar Understanding the role of RNA quality control in FSHD

The Chris Carrino Foundation, in conjunction with Friends of FSHD Research, is proud to continue funding for the Dr Suja Janaggathan Lab at The University of Colorado. We have just approved funding of year two of this project, with our portion amounting to $46,344.50.

Dr. Amy Campbell from the Janaggathan lab provides us with a synopsis of this important work.

Understanding the role of RNA quality control in FSHD

Written by Amy Campbell, PhD

Genes are sequences of DNA that contain instructions for the cell. When and where genes are turned on or off must be carefully controlled to ensure that the appropriate cellular instructions are being followed. When a gene is turned on, the DNA is copied into RNA, which is then used to make protein. Cells have many levels of “quality control” along the DNA -> RNA -> protein pipeline. One quality control pathway, called nonsense-mediated decay, detects and destroys incorrect or incomplete RNA before it can be used to make defective protein.

Understanding nonsense-mediated decay has become important for those patients, families, and scientists who seek to find therapies for facioscapulohumeral muscular dystrophy (FSHD), a devastating disease with no treatment or cure. FSHD is caused by mis-expression in skeletal muscle of the DUX4 gene, which is typically only turned on in the embryo. In 2015, Jagannathan and colleagues showed that when DUX4 is mis-expressed the effectiveness of the nonsense-mediated decay quality control pathway is reduced leading to a build-up of incorrect RNAs inside muscle cells. However, it was unclear whether these incorrect RNAs were turned into defective proteins, and if they contributed to FSHD pathogenesis.

Therefore, after Dr. Jagannathan established her own research group at the University of Colorado Anschutz Medical Campus in 2018, her team set out to determine whether the incorrect RNAs generated upon DUX4 mis-expression in muscle are made into defective proteins that have a toxic effect on the cell. In work jointly funded by the Chris Carrino Foundation for FSHD and Friends of FSH Research, the Jagannathan lab established a highly complex procedure called “ribosome footprinting” – that reads out the bits of RNA contained within molecular machines called ribosomes that are actively engaged in making RNAs into proteins – and used this technology to show that many incorrect RNAs are turned into defective, and potentially toxic, proteins in DUX4-expressing muscle cells. 

The Jagannathan lab went on to show that expressing one of the defective proteins in otherwise healthy muscle cells caused the cells to die. Notably, this defective protein is present in FSHD patient-derived muscle cells grown in culture. They are now exploring whether getting rid of the incorrect RNAs and defective proteins that build up as a result of DUX4 expression can prevent DUX4-mediated cell death.

These results not only provide new insights into FSHD pathobiology, the defective protein products identified by Dr. Jagannathan’s group are unique to DUX4-expressing cells and therefore could have utility as biomarkers for FSHD, helping to track disease status and/or progression.

Stay tuned for the publication of this work!