H. Lee Lab @ Johns Hopkins School of Medicine

PROJECT

There are over fifty repeat expansion disorders including Huntington's disease (HD), Fragile X syndrome (FXS), Myotonic Dystrophy (DM1/2), Friedreich's Ataxia (FRDA), spinocerebellar ataxias (SCAs), and amyotrophic lateral sclerosis / frontotemporal dementia (ALS/FTD) (Figure), and there’s no cure for most of them. These disorders arise when short DNA tandem repeats, which are normally present, expand due to unknown mechanisms. Typically, longer repeats are associated with more severe and earlier onset of the disease.

Understanding how these tandem repeats expand and contract, and how the long repeats contribute to the disease phenotypes will be foundational for conceptually novel therapies that prevent expansion and induce contraction of pathogenic repeats in diverse human diseases.

To tackle the diverse repeat expansion diseases, we will identify the novel factors involved in the repeat expansion that cause these devastating diseases. Moreover, we will investigate epigenetic mechanisms involved in expansion/contraction of long tandem repeats by recapitulating abnormal development and repeat expansion processes while differentiating patient-derived iPSCs toward the disease-specific cell types or organoids. By studying how the expanded repeat triggers the epigenetic misregulation, we will unveil the underlying mechanisms of the human diseases associated with repeat expansion in a new perspective with broader concepts of “epi”genetics - e.g., the functions of RNA-mediated non-canonical nucleic acid structures such as R-loops and G-quadruplexes in addition to DNA and histone modifications.