Year 2

The physiological template of our genome, called chromatin, is composed of DNA wrapped around histone proteins. In the process of development the genome is interpreted in a way that is dynamic, and yet, often heritable, to produce different specialized tissues and organs. A substantial portion of information that is required for proper interpretation of the genome is transmitted in a form of methylation of histones. Histone methylation marks are written by specific enzymatic activities, called methyltransferases. Different methyltransferases can activate or repress genes, and the right balance between the two is critical for proper execution of the developmental programs. Thus, not surprisingly, deregulation of methyltransferases leads to human disease, including congenital malformation and cancer.

Embryonic stem cells and other progenitor cells contain unique histone methylation signatures at genes that are dynamically activated or repressed in differentiation, depending on a specific cell type. With CIRM funding our research group made a significant progress in understanding how this unique methylation signatures are formed and properly maintained in embryonic and adult stem cells and resolved upon differentiation. We have identified novel chromatin proteins associated with methyltransferases in stem cells. We had shown that one of these proteins, called Jarid2, is responsible for directing the silencing methyltransferase to developmental genes and for regulating its activity. Depletion of Jarid2 affects developmental programs and leads to failure of differentiation.

We have also made headways in understanding how methyltransferase complexes connect to the signaling pathways orchestrating stem cell self-renewal and differentiation. Our work contributes to the basic science foundation that furthers our understanding of what makes stem cell a stem cell and what processes are involved in transitions from stem cells to specific, differentiated cell types.