Prof. Dr. Mariusz Nowacki

Our lab studies how RNA molecules can carry epigenetic information across generations in eukaryotic cells. We use ciliated protozoa as our model system because they perform one of the most dramatic epigenetic programs known: during development, they rebuild their genomes on a whole-genome scale by deleting, rearranging, and reassembling DNA. What makes this process so fascinating is that the offspring can’t do it alone. The parental cell has to “teach” the next generation how to assemble a functional genome. It does this using RNA-based guidance—essentially comparing the developing zygotic genome against the mother’s somatic genome and then making millions of highly specific decisions about what to keep, remove, or rearrange. The result is an extraordinarily large-scale yet remarkably precise example of RNA-mediated epigenetic inheritance.

https://nowackilab.org/

Mariusz Nowacki is a recipient of 2010 ERC Starting Grant and 2015 ERC Consolidator Grant.

Our group is part of the national research excellence network NCCR RNA and Disease.

Research

Our current research investigates how RNA-based information shapes genome development and epigenetic inheritance in ciliates, with a particular focus on the extraordinary whole-genome rearrangements that occur during sexual reproduction. We study how small-RNA pathways and Piwi–sRNA complexes guide the comparison between the maternal somatic genome and the developing zygotic genome, ensuring precise elimination of germline-limited DNA and faithful assembly of a functional somatic genome.

A major theme is how epigenetic signals are written, interpreted, and transmitted across generations—especially the roles of RNA-interacting proteins and RNA-guided chromatin and DNA modification pathways in establishing developmental “genome editing” programs.

We are also interested in the mechanistic basis and biological consequences of adenine DNA methylation (6mA) as a protective epigenetic mark during genome remodeling, including how such marks can be inherited and influence DNA retention versus deletion decisions.

By combining molecular genetics, biochemical interaction mapping, small-RNA profiling, and genome-scale sequencing, we aim to define general principles of RNA-mediated epigenetic regulation that extend beyond ciliates and illuminate how cells use RNA to control genome integrity and inheritance.

Figure 1. Scan RNA model – programming of developmental DNA deletions in Paramecium and Tetrahymena.
Parental somatic genome (MAC DNA) is entirely transcribed during sexual process (A). Meiotic micronucleus produces short, 25-30-nt dsRNA, so-called scnRNA that correspond to the entire germline genome (B), and are subsequently transported to the parental nucleus (C). Pairing between RNA copy of the parental genome and scnRNA takes place prior new MAC development, allowing selection of unpaired MIC-specific scnRNA (D). MIC-specific scnRNA target deletions of homologous DNA deletions in the developing MAC (E), leading to a mature new MAC. Blue boxes represent MAC-destined DNA, which in the MIC are separated from each other by germline-specific sequences (red boxes) like IESs or transposons.

Figure 2. Model for RNA guiding of genome rearrangements during macronuclear development in Oxytricha.
Bidirectional RNA transcription of all DNA nanochromosomes in the old, maternal macronucleus (MAC) before its degradation (A). Transport of these RNA transcripts to the newly developing macronucleus (B), where they may act as scaffolds to guide rearrangements (deletion, permutation and inversion) of corresponding micronuclear (MIC) DNA sequences (C). In this illustration, segments 2 and 3 are switched and segment 5 is inverted (number upside down).