Unravelling the role of differentially bound regions (DBRs) in murine hepatic and pancreatic differentiation and transdifferentiation

• Applicant: Dr. Dario Nicetto
• Subject Area: Developmental Biology ; Cell Biology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 242501497

Increasing evidence indicates epigenetic mechanisms as key players in embryonic development and cell reprogramming. Recently, Dr. Zaret and co-workers discovered differentially bound regions (DBRs) as megabase-scale, H3K9me3-enriched domains that are resistant to ectopic transcription factor binding and thereby impede cellular reprogramming. Yet the biological function of the DBRs remains unexplored. To unravel the role of DBRs, I will couple a comprehensive understanding of their deposition during embryonic development with their impact on cell transdifferentiation. Using the murine hepatic and pancreatic lineages as in vivo differentiation systems, I will employ the following strategy. First, using ChIP-Seq technology, I will precisely map H3K9me3-enriched DBRs during distinct stage of embryonic hepatocyte and pancreatic beta-cell development. The comparative analysis between the two lineages will reveal genomic differences in the establishment of the domains. Furthermore, this approach will lead to the identification of specific binding motifs on DNA, and molecular partners, enriched at the differential borders of the DBRs. Second, modulating H3K9me3-specific histone methyltransferases via gain- and loss-of-function approaches, both genetically and with small chemical compounds, I will investigate how DBRs can be manipulated to promote hepatocyte-to-beta-cell transdifferentiation. I expect the principles gained by these studies to be applicable to many cell systems. Moreover, the successful completion of this project will provide not only a dynamic picture of DBRs establishment during cell differentiation, but will also unravel their role in fixing and interconverting distinct cell identities, paving the way for possible therapeutic studies.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Dr. Kenneth S. Zaret