Xiajun (John) Li

Research

Specific Research Interests:

Acquisition and maintenance of DNA methylation genomic imprints; Epigenetic regulation in stem cells; Maintenance and differentiation of embryonic stem cells; LIN-12/Notch signaling and cardiovascular development.

Summary of Research Studies:

Genomic imprinting is essential for mammalian development. Consistent with this, a majority of cloned embryos die in utero, mainly from the failure to re-establish proper genomic imprints. Cell-based therapies offer great hopes for various degenerative diseases, including Alzheimer’s disease and diabetes. Embryonic stem (ES) cells derived from nuclear transfer experiments and induced pluripotent stem (iPS) cells reprogrammed from adult cells are candidates for this therapeutic approach. However, they all have genomic imprinting defects which can inhibit differentiation and may even cause cancer. Recently, it was reported that dysregulation of the Dlk1-Dio3 imprinted domain is the only notable difference between ES cells and iPS cells (Stadtfeld, M. et al. Nature, 2010). Indeed, hypermethylation and aberrant expression of the imprinted genes were observed at the Dlk1-Dio3 imprinted region in iPS cells Therefore, it is important to know how to manipulate the genomic imprinting machinery in pluripotent stem cells including iPS and ntES cells so that proper development of different lineages of cells can be achieved for therapeutic applications.

The current major focus of our lab is to analyze acquisition and maintenance of genomic imprinting in stem cells as well as in mouse embryos. Recently, we discovered that Zfp57 is highly enriched in ES cells and is a key regulator in genomic imprinting at multiple imprinted regions including the Dlk1-Dio3 domain. Loss of Zfp57 results in loss of DNA methylation genomic imprints at these imprinted regions. Consistent with our finding, mutations in human Zfp57 result in hypomethylation at multiple imprinted regions. Currently we are actively investigating the underlying mechanisms of ZFP57-associated complexes in the acquisition and maintenance of DNA methylation imprints in both mouse embryos and ES cells.

Dysregulation of imprinting genes can lead to cancer, neurological diseases, diabetes and other kinds of human diseases. Indeed, mutations in human ZFP57 are associated with transient neonatal diabetes, congenital heart defects and abnormal development of the nervous system. We have independently discovered that Zfp57 mutant mouse is obese and display similar defects in the cardiovascular system. Thus, our Zfp57 mutant mouse could serve as useful animal models for complex human diseases such as obesity, diabetes and cardiovascular diseases.

For more information, please visit the Li Laboratory website.