The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

Compacting and organizing up to 2 meters of DNA into a nucleus of roughly 10 microns provides a formidable barrier to molecular processes such as transcription, replication, and recombination. However, the seemingly rigid chromatin structure is actually quite dynamic and regulable such that cells can utilize the structure to render regions of the genome either more amenable or more refractory to molecular processes. It is now recognized that dis-regulation of these epigenetic regulatory processes are an underlying factor in many human disorders. To better understand the epigenetic regulation of the genome we are developing Xenopus laevis as a model developmental system for investigating the establishment and maintenance of epigenetic marks, and their subsequent effects on gene and genome regulation.

One striking example of epigenetic dis-regulation is Facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant myopathy characterized by progressive atrophy of the facial, shoulder, and upper arm muscles. The FSHD genetic defect is not a mutation in a protein-encoding gene, but a deletion within the diverse array of tandem DNA repeats (D4Z4) specifically localized proximal to the chromosome 4q subtelomere. In addition, the FSHD deletion is exclusively associated with one of two subtelomere variants, 4q35A, (keeping in mind that the majority of people with 4q35A do not have the repeat lesion or FSHD) and never with 4q35B. Overall, the circumstances presented by FSHD suggest the molecular mechanisms likely involve an epigenetic misregulation of gene expression.

Our work on FSHD has two parts; understanding how the D4Z4 array and the 4q35 subtelomere regulate gene expression (cause of the dis-regulation) and how dis-regulation of a gene(s) leads to FSHD pathology (effect of the dis-regulation). We use the highly efficient Xenopus transgenic technology to generate transgenic Xenopus models for both investigations. In addition, unique aspects of Xenopus development allow us to further distinguish between disease establishment and progression.

Recently, we have begun a collaborative project investigating the epigenetics of behavior using the western honeybee as a social model. Unlike Drosophila, the honeybee contains a true, functional DNA methylation system similar to vertebrates making it the insect of choice for epigenetic studies.