Research

Research in the Peter and Takako Jones lab

Research in the Peter and Takako Jones lab

Peter and Takako Jones function as Co-PIs, combining expertise in gene regulation, biochemistry and chromatin with expertise in cell biology, developmental biology and molecular biology. Together we investigate epigenetic mechanisms of gene regulation focusing on the combined roles of DNA methylation, Polycomb Group proteins, histone post-translational modifications and noncoding RNAs.

We use a wide range of approaches, including biochemistry, cell biology, developmental biology, proteomics and epigenomics, to investigate the epigenetic mechanisms that function during normal muscle development and establish and maintain disease states. In addition, our experimental approaches utilize several different model organisms (mouse, Drosophila, C. elegans, and Xenopus) to augment our work in primary human cell culture models and in vitro systems. Overall, we aim to design therapeutic approaches targeting the epigenetic regulatory mechanisms involved in human disease with a particular focus on myopathies. Our research has three main areas:

Epigenetics of muscle development and disease

We use Facioscapulohumeral muscular dystrophy (FSHD) as a model to investigate epigenetic mechanisms of gene regulation. The genetic criteria for FSHD are merely disease permissive, however, all forms of clinical FSHD exhibit epigenetic dysregulation of the chromosome 4q35 D4Z4 macrosatellite. 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.

Engineering novel disease models for therapeutic development and preclinical testing

We are designing human cellular as well as animal models of FSHD, including mouse, Drosophila and C. elegans, for therapeutic development and pre-clinical testing. These models are based on aberrant expression of DUX4-FL and/or FRG1, two genes important for development and implicated in mediating FSHD pathophysiology. These FSHD disease relevant models are used to test small molecule, ncRNA, and CRISPR-based therapeutic approaches.

RNA-binding proteins involved in development and disease

We focus on two highly conserved proteins, FRG1 and MeCP2, which we have identified as RNA-binding proteins. In addition to interacting with select mRNAs, FRG1 is also an actin bundling protein critical for muscle development and a direct transcriptional target of the DUX4-FL transcription factor. MeCP2 is an epigenetic regulator critical for neuronal development and the gene most commonly mutated in Rett Syndrome.