000243385 001__ 243385
000243385 005__ 20230212174148.0
000243385 0247_ $$2CORDIS$$aG:(EU-Grant)894489$$d894489
000243385 0247_ $$2CORDIS$$aG:(EU-Call)H2020-MSCA-IF-2019$$dH2020-MSCA-IF-2019
000243385 0247_ $$2originalID$$acorda__h2020::894489
000243385 035__ $$aG:(EU-Grant)894489
000243385 150__ $$aStructural investigation of interplay between epigenetics, transcriptional regulation and DNA damage$$y2020-04-01 - 2022-03-31
000243385 372__ $$aH2020-MSCA-IF-2019$$s2020-04-01$$t2022-03-31
000243385 450__ $$aEPIDNA$$wd$$y2020-04-01 - 2022-03-31
000243385 5101_ $$0I:(DE-588b)5098525-5$$2CORDIS$$aEuropean Union
000243385 680__ $$aIn eukaryotic cells, gene expression is regulated by a complex interplay between a number of factors, from large-scale chromatin accessibility to inducible enhancers or repressors to local DNA modifications, changes in nucleosome architecture and specific histone markers. These finely tuned factors coordinate embrional development, response to stimuli and changes in cell fate. At the same time, this regulatory network has to robustly accommodate random events, most notably the presence of DNA damage and the action of DNA repair factors. While recent reports suggest this interplay is not always smooth, our mechanistic understanding of the underlying processes is severely limited, highlighting the need for quantitative approaches that will yield predictive models.

In this proposal, I plan to investigate three aspects of this interplay that recently came into the spotlight. Firstly, an integrative computational and experimental approach will be used to quantify the positioning effect resulting from a range of common DNA modifications: regulatory base variants that can be used to enforce specific nucleosome patterns, and damage byproducts that would thereby interfere with DNA repair through altered exposure to the environment. Secondly, a number of transcription factors will be systematically assessed to detect ones sensitive to the presence of the most common oxidative lesion, 8-oxoguanine, to identify possible direct cross-talk between oxidative stress and transcriptional regulation at oxidative hot spots. Finally, a multiscale quantum/classical study will explore the thermodynamics, mechanism of formation and possible nucleosomal locations of covalent histone-DNA cross-links that were recently postulated to both mediate the regulatory role of 5-formylcytosine and accelerate strand scission at abasic sites.
000243385 909CO $$ooai:juser.fz-juelich.de:899825$$pauthority$$pauthority:GRANT
000243385 909CO $$ooai:juser.fz-juelich.de:899825
000243385 980__ $$aG
000243385 980__ $$aCORDIS
000243385 980__ $$aAUTHORITY