Research in the Peter and Takako Jones lab

Research in the Peter and Takako Jones lab

Drs. Peter and Takako Jones function as Co-PIs, combining expertise in epigenetic gene regulation, biochemistry and chromatin biology with expertise in cell biology, developmental biology and molecular biology to address important questions in FSHD. Overall, we investigate the epigenetic dysregulation leading to pathogenic gene expression in FSHD to understand disease mechanisms, identify therapeutic targets, design novel therapies, and improve FSHD diagnostics.  Our research has four main areas:

Epigenetics of muscle development and disease

We use FSHD (facioscapulohumeral muscular dystrophy) as a model to investigate epigenetic mechanisms of gene regulation. The genetic criteria for FSHD are merely disease permissive, however, all forms of FSHD exhibit epigenetic dysregulation of the chromosome 4q35 D4Z4 macrosatellite leading to aberrant expression of the pathogenic DUX4 gene from within the array.  The epigenetic mechanisms differentially regulated in FSHD include DNA methylation, histone post-translational modifications, Polycomb Group proteins, lncRNAs, RNA dependent DNA methylation, and nuclear organization.  Thus, FSHD provides an outstanding model for investigating epigenetic mechanisms that have global genome implications.

Engineering novel disease models for therapeutic development and preclinical testing

We are designing human cellular models as well as murine and porcine models of FSHD for therapeutic development and pre-clinical testing. These models are based on aberrant expression of a transgenic human DUX4 gene from either a floxed cassette or a native human chromosome 4q35 transgene structure.  These FSHD disease relevant models are used to test small molecule drugs, antisense oligonucleotide, and CRISPR-based therapeutic approaches.

FSHD therapeutics

FSHD is a dominant gain-of-function disease amenable to numerous therapeutic technologies.  Our lab is developing two approaches, 1) CRISPR-inhibition gene therapy to silence pathogenic gene expression, and 2) identification and optimization of small molecule drugs that inhibit pathogenic gene expression.

FSHD diagnostics

FSHD is very difficult to accurately diagnose clinically and, due to the complex genetics involved at the disease locus, current genetic diagnostics are expensive and not widely accessible.  We have developed a novel FSHD diagnostic based on the differential epigenetic signatures among FSHD1, FSHD2, and healthy (or non-FSHD) individuals.  Importantly, this PCR based protocol can be performed on genomic DNA isolated from saliva.  Thus, one can collect samples for testing using saliva collection kits sent through the mail to anywhere in the world.  In addition, this decreases the cost of FSHD diagnostics by about 10-fold.  This affordable and accessible FSHD testing is currently available through our lab as a research test (not for clinical use) and we are in the process of transitioning to a clinically relevant and CLIA-approved test.