Prof. Dr. Mariusz Nowacki

Epigenetic mechanisms of complex genome editing in eukaryotes

Link to Nowacki lab website

My lab focuses on the mechanisms of RNA-mediated epigenetic inheritance in eukaryotic cells. Using ciliated protozoa as model organisms gives us the opportunity to study the very complex epigenetic phenomena accompanying the whole-genome scale developmental DNA rearrangements, where the parental cell must provide sufficient amount of information in order to produce a fully functional progeny. This involves a RNA-mediated comparison of the developing zygotic genome with the maternal somatic genome in an extraordinarily massive and precise manner.

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

My lab focuses on the mechanisms of RNA-mediated epigenetic inheritance in eukaryotic cells. One of the most wonderful epigenetic phenomena known to researchers are those accompanying the whole-genome scale developmental DNA rearrangements in ciliated protozoans. This involves a comparison of the developing zygotic genome with the maternal somatic genome in an extraordinarily massive and precise manner. In ciliates, germline and somatic functions are ensured by two different kinds of nuclei, the diploid micronucleus and a DNA rich macronucleus. Sexual events are initiated by meiosis of the micronucleus, and following fertilization, the parental macronucleus is lost and replaced by a new one that develops from the zygotic nucleus.

The development of a new macronucleus involves extensive rearrangements of the germline genome, including elimination of transposons and other repeated sequences and the precise excision of numerous single-copy Internal Eliminated Sequences (IESs) from coding and non-coding sequences. Genome-wide rearrangements discard nearly all non-genic DNA, resulting in streamlined gene-rich genomes (in Paramecium for instance, ~40,000 genes in only 72 Mb). In some cases, for example in the ciliate Oxytricha, rearrangement of the remaining somatic DNA segments (Macronucleus Destined Segments, or MDSs) also occurs by reordering or inversion (the so-called “scrambled genes”).

The amazingly high degree of specificity and reproducibility suggests a role for some general mechanism of programming of rearrangements, assuring its absolute accuracy and recurrence. The parental ciliate cell must provide sufficient amount of information in order to produce a fully functional new macronucleus. The mechanisms, which allow the cell to perfectly recognize hundreds of thousands of DNA sequences destined for elimination remains largely unknown. However, the discovery of homology-dependent maternal effects that can modify rearrangements patterns has shed some light on the molecular basis of the programming process. It now seems clear that epigenetic phenomena play a central role in the mechanism of programming of developmental genome rearrangements in ciliates. The developing genome reproduces the rearrangements present in the parental nucleus through an RNA-mediated trans-nuclear comparison of genomes (see figures 1 and 2).

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).

Nowacki Lab

Post Docs

PhD students

Master students

Technicians

2016: ERC Consolidator Grant

2015 - present: Professor of Genetics, University of Bern, Switzerland

2014 - present: Member of the NCCR RNA & Disease

2010: ERC Starting Grant

2010 - 2014: Assistant Professor, University of Bern, Switzerland

2010: Habilitation, University of Bern, Switzerland

2005 - 2010: Postdoctoral researcher, Princeton University, USA

2005: PhD, École Normale Supérieure and University of Paris VI, Paris, France

Number of items: 18.

Journal Article

Allen, Sarah Elizabeth; Hug, Iris Sandra; Pabian, Sylwia Weronika; Rzeszutek, Iwona Maria; Höhener, Cristina; Nowacki, Mariusz (2017). Circular Concatemers of Ultra-Short DNA Segments Produce Regulatory RNAs. Cell, 168(6), 990-999.e7. Cell Press 10.1016/j.cell.2017.02.020

Allen, Sarah Elizabeth; Nowacki, Mariusz (2017). Necessity Is the Mother of Invention: Ciliates, Transposons, and Transgenerational Inheritance. Trends in genetics, 33(3), pp. 197-207. Elsevier Current Trends 10.1016/j.tig.2017.01.005

Swart, Estienne Carl; Serra, Valentina; Petroni, Giulio; Nowacki, Mariusz (2016). Genetic Codes with No Dedicated Stop Codon: Context-Dependent Translation Termination. Cell, 166(3), pp. 691-702. Cell Press 10.1016/j.cell.2016.06.020

Bracht, John R; Wang, Xing; Shetty, Keerthi; Chen, Xiao; Uttarotai, Grace J; Callihan, Evan C; McCloud, Sierra S; Clay, Derek M; Wang, Jingmei; Nowacki, Mariusz; Landweber, Laura F (2016). Chromosome fusions triggered by noncoding RNA. RNA biology, pp. 1-12. Landes Bioscience 10.1080/15476286.2016.1195940

Swart, Estienne Carl; Nowacki, Mariusz (2015). The eukaryotic way to defend and edit genomes by sRNA-targeted DNA deletion. Annals of the New York Academy of Sciences, 1341, pp. 106-114. Blackwell 10.1111/nyas.12636

Ignarski, Michael; Singh, Aditi; Swart, Estienne Carl; Arambasic, Miroslav; Sandoval, Pamela Yohanna de Lourdes; Nowacki, Mariusz (2014). Paramecium tetraurelia chromatin assembly factor-1-like protein PtCAF-1 is involved in RNA-mediated control of DNA elimination. Nucleic acids research, 42(19), pp. 11952-11964. Information Retrieval Ltd. 10.1093/nar/gku874

Swart, Estienne Carl; Wilkes, Cyril Denby; Sandoval, Pamela Yohanna de Lourdes; Arambasic, Miroslav; Sperling, Linda; Nowacki, Mariusz (2014). Genome-wide analysis of genetic and epigenetic control of programmed DNA deletion. Nucleic acids research, 42(14), pp. 8970-8983. Information Retrieval Ltd. 10.1093/nar/gku619

Sandoval, Pamela Yohanna de Lourdes; Swart, Estienne Carl; Arambasic, Miroslav; Nowacki, Mariusz (2014). Functional Diversification of Dicer-like Proteins and Small RNAs Required for Genome Sculpting. Developmental cell, 28(2), pp. 174-188. Cell Press 10.1016/j.devcel.2013.12.010

Aeschlimann, Samuel H.; Jönsson, Franziska; Postberg, Jan; Stover, Nicholas A.; Petera, Robert L.; Lipps, Hans-Joachim; Nowacki, Mariusz; Swart, Estienne Carl (2014). The Draft Assembly of the Radically Organized Stylonychia lemnae Macronuclear Genome. Genome biology and evolution, 6(7), pp. 1707-1723. Oxford University Press 10.1093/gbe/evu139

Arambasic, Miroslav; Sandoval, Pamela Yohanna de Lourdes; Höhener, Cristina; Singh, Aditi; Swart, Estienne Carl; Nowacki, Mariusz (2014). Pdsg1 and Pdsg2, novel proteins involved in developmental genome remodelling in Paramecium. PLoS ONE, 9(11), e112899. Public Library of Science 10.1371/journal.pone.0112899

Fuhrmann, Gloria; Swart, Estienne; Nowacki, Mariusz; Lipps, Hans J. (2013). RNA-dependent genome processing during nuclear differentiation: the model systems of stichotrichous ciliates. Epigenomics, 5(2), pp. 229-236. Future Medicine 10.2217/epi.13.15

Swart, Estienne C.; Bracht, John R.; Magrini, Vincent; Minx, Patrick; Chen, Xiao; Zhou, Yi; Khurana, Jaspreet S.; Goldman, Aaron D.; Nowacki, Mariusz; Schotanus, Klaas; Jung, Seolkyoung; Fulton, Robert S.; Ly, Amy; McGrath, Sean; Haub, Kevin; Wiggins, Jessica L.; Storton, Donna; Matese, John C.; Parsons, Lance; Chang, Wei-Jen; ... (2013). The Oxytricha trifallax macronuclear genome: a complex eukaryotic genome with 16,000 tiny chromosomes. PLoS biology, 11(1), e1001473. Public Library of Science 10.1371/journal.pbio.1001473

Fang, Wenwen; Wang, Xing; Bracht, John R.; Nowacki, Mariusz; Landweber, Laura F. (2012). Piwi-Interacting RNAs Protect DNA against Loss during Oxytricha Genome Rearrangement. Cell, 151(6), pp. 1243-1255. Cambridge, Mass.: Cell Press 10.1016/j.cell.2012.10.045

Nowacki, Mariusz; Shetty, Keerthi; Landweber, Laura F. (2011). RNA-Mediated Epigenetic Programming of Genome Rearrangements. Annual review of genomics and human genetics, 12(1), pp. 367-389. Palo Alto, Calif.: Annual Reviews Inc. 10.1146/annurev-genom-082410-101420

Nowacki, Mariusz; Haye, Joanna E.; Fang, Wenwen; Vijayan, Vikram; Landweber, Laura F. (2010). RNA-mediated epigenetic regulation of DNA copy number. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 107(51), pp. 22140-22144. Washington, D.C.: National Academy of Sciences NAS 10.1073/pnas.1012236107

Book Section

Allen, Sarah Elizabeth; Nowacki, Mariusz (2016). RNA-Guided Genome Editing. In: Witzany, Guenther; Nowacki, Mariusz (eds.) Biocommunication of Ciliates (pp. 35-50). Cham: Springer 10.1007/978-3-319-32211-7_3

Book

Nowacki, Mariusz; Witzany, Guenther (eds.) (2016). Biocommunication of Ciliates. Cham: Springer 10.1007/978-3-319-32211-7

Report

Almouzni, Geneviève; Altucci, Lucia; Amati, Bruno; Ashley, Neil; Baulcombe, David; Beaujean, Nathalie; Bock, Christoph; Bongcam-Rudloff, Erik; Bousquet, Jean; Braun, Sigurd; Paillerets, Brigitte Bressac-de; Bussemakers, Marion; Clarke, Laura; Conesa, Ana; Estivill, Xavier; Fazeli, Alireza; Grgurević, NeŽa; Gut, Ivo; Heijmans, Bastiaan T; Hermouet, Sylvie; ... (2014). Relationship between genome and epigenome - challenges and requirements for future research BioMed Central 10.1186/1471-2164-15-487

This list was generated on Sun Apr 23 21:37:09 2017 CEST.