Xist-mediated nucleation of heterochromatin and (epi)genetic stability of the inactive X chromosome

• Applicant: Dr. Stefan Pinter
• Subject Area: General Genetics and Functional Genome Biology
• Term: from 2010 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 187885059

Human cancer is a complex disease triggered by a combination of oncogene activation and tumor suppressor gene inactivation, changes that are increasingly attributed not only to genetic but also epigenetic instability. Numerous clinical trials for a new generation of drugs targeting chromatin modifying complexes are underway and existing "epigenetic drugs" such as DNA methylation or histone deacetylation inhibitors are adopted for a wider selection of cancer types. Since the therapeutic benefit of reactivating a tumor suppressor in cancer cells is compromised if previously untransformed cells acquire a tumorigenic epigenetic program, the stability of the untransformed epigenetic state during treatment is of paramount importance.The inactive X chromosome (Xi) in female mammals is a classic example of epigenetics and can serve as a useful paradigm towards understanding the molecular mechanisms that determine the stability of euchromatin and heterochromatin. This proposal uses massively parallel sequencing technology, custom bioinformatics and mouse genetics to address three major questions in the field: 1.) How are inactivating chromatin marks spread over the chromosome when the future Xi is established? 2.) What role do specific DNA sequences play in establishing and maintaining the inactive state of the Xi? 3.) How does the loss of Xist RNA, the critical factor in Xi establishment, impact the genetic and epigenetic stability of the Xi in the maintenance phase? The answers to these questions will provide basic insights into how Xi heterochromatin is organized, test whether repetitive elements shape Xi chromatin, and may help to identify novel X-linked oncogenes.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Jeannie T. Lee