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Éric Meyer

Programmed genome rearrangements in ciliates

Background


The ciliate Paramecium tetraurelia provides a unique opportunity to study programmed genome rearrangements, and their epigenetic regulation by non-coding RNAs, in a unicellular model. During the development of the somatic macronucleus from the germline micronucleus, transposable elements and other repeated sequences are eliminated in an imprecise manner, often resulting in the fragmentation of chromosomes, and over 50,000 short, single-copy internal eliminated sequences (IESs) are very precisely excised from genes and intergenic regions. Our research activities focus on (i) the molecular mechanisms involved in these site-specific recombination events, and (ii) the epigenetic mechanisms through which cells can specifically recognize a very large number of different IESs that are only marked by two flanking TA dinucleotides and a poorly conserved consensus sequence extending over a few bases at each end.

Research highlights

After several years spent characterizing IES excision intermediates and products, and the geometry of double-strand breaks initiating the process, the sequencing of the P. tetraurelia macronuclear genome has allowed us to identify some of the proteins involved. Excision depends on a developmentally regulated, domesticated transposase of the piggyBac family, which appears to be the endonuclease responsible for both types of genome rearrangements. We have further shown that the non-homologous end-joining pathway, including a true DNA-PKcs ortholog, is involved in the repair of double-strand breaks.
The study of homology-dependent maternal effects that regulate alternative rearrangements of the germline genome has led us to the discovery of two small RNA pathways relying on distinct Dicer-like, Piwi, and accessory proteins. One of these produces massive amounts of scnRNAs from the germline genome during meiosis, similar to metazoan piRNAs. A natural genomic subtraction with maternal somatic RNAs appears to select the scnRNAs that will target deletions in the developing macronucleus, resulting in non-Mendelian inheritance of rearrangement patterns.
A third theme was recently inspired by the finding that ‘translatable’ introns are universally counter-selected in intron-rich eukaryotic genomes. The bias, which was first discovered in P. tetraurelia because of the very short size of its introns, suggests that eukaryotes rely on nonsense-mediated mRNA decay to compensate for suboptimal splicing efficiency, as experimentally verified by the knockdown of UPF genes in Paramecium.

Orias E, Singh DP, Meyer E. Genetics and epigenetics of mating type determination in Paramecium and Tetrahymena. Annu Rev Microbiol. 2017;71:133-156. doi:10.1146/annurev-micro-090816-093342.

Saudemont B, Popa A, Parmley JL, Rocher V, Blugeon C, Necsulea A, Meyer E, Duret L. The fitness cost of mis-splicing is the main determinant of alternative splicing patterns. Genome Biol. 2017;18(1):208. doi:10.1186/s13059-017-1344-6.

Singh DP, Saudemont B, Guglielmi G, Arnaiz O, Goût J-F, Prajer M, et al. Genome-defence small RNAs exapted for epigenetic mating-type inheritance. Nature 2014;509:447–52. doi:10.1038/nature13318. Selected by Faculty of 1000. /pdf

Arnaiz O, Mathy N, Baudry C, Malinsky S, Aury J-M, Denby Wilkes C, et al. The Paramecium Germline Genome Provides a Niche for Intragenic Parasitic DNA: Evolutionary Dynamics of Internal Eliminated Sequences. PLoS Genetics 2012;8:e1002984. doi:10.1371/journal.pgen.1002984. /pdf

Baudry C, Malinsky S, Restituito M, Kapusta A, Rosa S, Meyer E, et al. PiggyMac, a domesticated piggyBac transposase involved in programmed genome rearrangements in the ciliate Paramecium tetraurelia. Genes & Development 2009;23:2478–83. doi:10.1101/gad.547309. Selected by Faculty of 1000 /pdf

Jaillon O, Bouhouche K, Gout J-F, Aury J-M, Noel B, Saudemont B, et al. Translational control of intron splicing in eukaryotes. Nature 2008;451:359–62. doi:10.1038/nature06495. Selected by Faculty of 1000. /pdf



Paramecium tetraurelia
Paramecium tetraurelia
Paramecium cells during conjugation
Paramecium cells during conjugation
Nature Cover 22nd May 2014
Nature Cover 22nd May 2014
Stages during Autogamy of Paramecium cells / Simran Bhullar
Stages during Autogamy of Paramecium cells / Simran Bhullar