The Niehrs laboratory studies regulation of DNA methylation, which plays important roles in development & disease. We have recently demonstrated a role for long non-coding RNAs and R-loop DNA:RNA hybrids in DNA methylation (Arab et al. 2014; Arab et al. 2019). In an ERC-funded project, we now aim to elucidate the mechanisms of DNA demethylation as well as the role played by long non-coding RNAs and R-loops in its regulation. See also https://www.imb.de/research/niehrs/research
Candidates will make use of mouse embryonic stem cells (ESCs) to interrogate genome-wide the role of ncRNAs and R-loops in targeting GADD45a and the DNA demethylation machinery in the genome. We will use CRISPR/CAS9 mediated ESC mutants, as well as ChIP-seq, RNA-seq, bisulfite-seq to carry out multi- dimensional data analysis to address:
- Where in the genome does demethylation occur?
- What are the molecular determinants in ncRNA & Rloops involved in targeting?
- What are the cofactors involved?
- The project will involve strong interaction with a Computational Biologist
- PhD & publications in a relevant field
- Sound experience in molecular biology
- Familiarity with Omics techniques or –analysis, or with ncRNAs or R-loops is advantageous
- Excellent communication skills and good team spirit with the ability to solve problems independently
- Fluent in English (spoken and written)
Publications Relevant to the Project
(#indicates joint correspondence)
Arab K, Karaulanov E, Musheev M, Trnka P, Schäfer A, Grummt I# and Niehrs C# (2019) GADD45A binds R-loops and recruits TET1 to CpG island promoters. Nat Genet, 51:217–223
Schäfer A, Mekker B, Mallick M, Vastolo V, Karaulanov E, Sebastian D, von der Lippen C, Epe B, Downes DJ, Scholz C and Niehrs C (2018) Impaired DNA demethylation of C/EBP sites causes premature aging. Genes Dev, 32:742–762
Arab K, Park YJ, Lindroth AM, Schäfer A, Oakes C, Weichenhan D, Lukanova A, Lundin E, Risch A, Meister M, Dienemann H, Dyckhoff G, Herold-Mende C, Grummt I#, Niehrs C# and Plass C# (2014) Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A. Mol Cell, 55:604–614
Niehrs C and Schäfer A (2012) Active DNA demethylation by Gadd45 and DNA repair. Trends Cell Biol, 22:220–227
Barreto G, Schäfer A, Marhold J, Stach D, Swaminathan SK, Handa V, Döderlein G, Maltry N, Wu W, Lyko F and Niehrs C (2007) Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature, 445:671–675