Skip to main content

Functions and mechanism of active DNA demethylation

Objective

Epigenetic gene regulation is of central importance for development and disease. Despite dramatic progress in epigenetics during the past decade, DNA demethylation remains one of the last big frontiers and very little is known about it. DNA demethylation is a widespread phenomenon and occurs in plants as well as in animals, during development, in the adult, and during somatic cell reprogramming of pluripotency genes. The molecular identity of the DNA demethylase in animal cells remained unresolved and has hampered progress in the field for decades. In 2007 we published that Growth Arrest and DNA Damage 45 a (Gadd45a) is a key player in active DNA demethylation, which opened new avenues in the study of this elusive process. The goal of this project is to further analyze the mechanism of DNA demethylation as well as the role played by Gadd45 in development. Given the many unresolved questions in this burgeoning field, our work promises to be ground-breaking and therefore have a profound impact in unraveling one of the least understood processes of gene regulation. Specifically we will address the following points. I) The biological role of Gadd45 mediated DNA demethylation in mouse embryos and adults is unknown. We have obtained mouse mutants for Gadd45a,b, and g and we will analyze them for developmental defects and dissect the methylation regulation of relevant genes. II) The targeting mechanism by which Gadd45 is binding to and demethylating specific sites in the genome is a central unresolved issue. We have identified a candidate DNA binding protein interacting with Gadd45 and we will analyze its role in site specific targeting of DNA demethylation in vitro and in mouse. III) We found that Gadd45 is an RNA binding protein and we will therefore analyze how non-coding RNAs are involved in targeting and/or activating Gadd45 during DNA demethylation.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/rna
  • /natural sciences/biological sciences/genetics and heredity/genome
  • /medical and health sciences/clinical medicine/embryology

Call for proposal

ERC-2009-AdG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

INSTITUT FUR MOLEKULARE BIOLOGIE GGMBH
Address
Ackermannweg 4
55128 Mainz
Germany
Activity type
Research Organisations
EU contribution
€ 2 201 000
Principal investigator
Heinz Christof Niehrs (Prof.)
Administrative Contact
Franziska Hornig (Ms.)

Beneficiaries (2)

INSTITUT FUR MOLEKULARE BIOLOGIE GGMBH
Germany
EU contribution
€ 2 201 000
Address
Ackermannweg 4
55128 Mainz
Activity type
Research Organisations
Principal investigator
Heinz Christof Niehrs (Prof.)
Administrative Contact
Franziska Hornig (Ms.)
DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG

Participation ended

Germany
EU contribution
€ 175 000
Address
Im Neuenheimer Feld 280
69120 Heidelberg
Activity type
Research Organisations
Administrative Contact
Elke Luksch (Ms.)