Helmholtz Professorship Molecular Biology of the Cell II
Prof. Dr. Ingrid Grummt
Our group identifies, characterizes and exploits the molecular mechanisms that control gene expression at the genetic and epigenetic level, aiming to understand the chain of events by which external signals are transferred into the cell nucleus to regulate transcription of specific genes. Focussing on the role of nuclear noncoding RNA (ncRNA) in chromatin structure and epigenetic regulation, we found that ncRNA has an impact on many chromatin-mediated processes, linking both RNA and chromatin fields. We have discovered a novel RNA-based strategy for epigenetic programming, showing that ncRNAs are capable of forming DNA:RNA triplexes with regulatory gene sequences. These triplex structures are specifically recognized by the DNA methyltransferase DNMT3b, thereby inducing DNA methylation and transcriptional silencing. Other ncRNAs guide histone modifying enzymes to specific genomic sites, demonstrating that ncRNAs can act as selective ligands for chromatin modifying enzymes. Deciphering novel epigenetic and metabolic control mechanisms of gene expression will reveal how epigenetic defects cause human diseases and will be instrumental in facilitating therapeutic strategies in the future.
Evidence from a variety of experimental systems demonstrates that non-coding RNAs (ncRNAs) play a significant role in the control of gene expression and epigenetic regulation. It seems that ncRNAs are numerous and highly adapted in roles that require specific nucleic acid recognition without complex catalysis, such as in guiding RNA modifications or in directing post-transcriptional regulation of gene expression and chromatin structure. We intend to identify ncRNAs involved in the regulation of chromatin and transcription and will investigate the mechanism by which these ncRNAs regulate the function of transcription factors and chromatin modifying enzymes. We will perform genome-wide analyses to explore with which proteins these regulatory RNAs are associated and will validate their role in key biological processes. We expect that in the long term, these studies will lead to an understanding of the mechanisms that propagate a specific chromatin structure through cell division and will provide mechanistic insights into the functions of ncRNAs in transcriptional regulation.
Schmitz, K.-M., Mayer, C., Postepska, A. & Grummt, I. (2010). Triplex formation between noncoding RNA and DNA targets DNMT3b to regulatory gene regions. Genes&Dev. 24, 2265-2269.
Chen S, Seiler J, Santiago-Reichelt M, Felbel K, Grummt I, Voit R (2013) Repression of RNA Polymerase I upon stress is caused by inhibition of RNA-dependent deacetylation of PAF53 by SIRT7. Mol Cell 52, 303-313.
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, Plass C (2014) Long noncoding RNA TARID directs demthylation and activation of the tumor suppressor TCF21 via GADD45a. Mol Cell 55, 604-614.
Bierhoff H, Dammert MA, Brocks D, Dambacher S, Schotta G, Grummt I (2014) Quiescence-induced LncRNAs triggger H4K20 trimethylation and transcriptional silencing. Mol Cell 54, 675-682.