Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

Experimental evolution links post-transcriptional regulation to Leishmania fitness gain

L. Piel, KS. Rajan, G. Bussotti, H. Varet, R. Legendre, C. Proux, T. Douché, Q. Giai-Gianetto, T. Chaze, T. Cokelaer, B. Vojtkova, N. Gordon-Bar, T. Doniger, S. Cohen-Chalamish, P. Rengaraj, C. Besse, A. Boland, J. Sadlova, JF. Deleuze, M....

. 2022 ; 18 (3) : e1010375. [pub] 20220316

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

The protozoan parasite Leishmania donovani causes fatal human visceral leishmaniasis in absence of treatment. Genome instability has been recognized as a driver in Leishmania fitness gain in response to environmental change or chemotherapy. How genome instability generates beneficial phenotypes despite potential deleterious gene dosage effects is unknown. Here we address this important open question applying experimental evolution and integrative systems approaches on parasites adapting to in vitro culture. Phenotypic analyses of parasites from early and late stages of culture adaptation revealed an important fitness tradeoff, with selection for accelerated growth in promastigote culture (fitness gain) impairing infectivity (fitness costs). Comparative genomics, transcriptomics and proteomics analyses revealed a complex regulatory network associated with parasite fitness gain, with genome instability causing highly reproducible, gene dosage-independent and -dependent changes. Reduction of flagellar transcripts and increase in coding and non-coding RNAs implicated in ribosomal biogenesis and protein translation were not correlated to dosage changes of the corresponding genes, revealing a gene dosage-independent, post-transcriptional mechanism of regulation. In contrast, abundance of gene products implicated in post-transcriptional regulation itself correlated to corresponding gene dosage changes. Thus, RNA abundance during parasite adaptation is controled by direct and indirect gene dosage changes. We correlated differential expression of small nucleolar RNAs (snoRNAs) with changes in rRNA modification, providing first evidence that Leishmania fitness gain in culture may be controlled by post-transcriptional and epitranscriptomic regulation. Our findings propose a novel model for Leishmania fitness gain in culture, where differential regulation of mRNA stability and the generation of modified ribosomes may potentially filter deleterious from beneficial gene dosage effects and provide proteomic robustness to genetically heterogenous, adapting parasite populations. This model challenges the current, genome-centric approach to Leishmania epidemiology and identifies the Leishmania transcriptome and non-coding small RNome as potential novel sources for the discovery of biomarkers that may be associated with parasite phenotypic adaptation in clinical settings.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22019174
003      
CZ-PrNML
005      
20220804135416.0
007      
ta
008      
220720s2022 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1371/journal.ppat.1010375 $2 doi
035    __
$a (PubMed)35294501
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Piel, Laura $u Institut Pasteur, Université de Paris, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France
245    10
$a Experimental evolution links post-transcriptional regulation to Leishmania fitness gain / $c L. Piel, KS. Rajan, G. Bussotti, H. Varet, R. Legendre, C. Proux, T. Douché, Q. Giai-Gianetto, T. Chaze, T. Cokelaer, B. Vojtkova, N. Gordon-Bar, T. Doniger, S. Cohen-Chalamish, P. Rengaraj, C. Besse, A. Boland, J. Sadlova, JF. Deleuze, M. Matondo, R. Unger, P. Volf, S. Michaeli, P. Pescher, GF. Späth
520    9_
$a The protozoan parasite Leishmania donovani causes fatal human visceral leishmaniasis in absence of treatment. Genome instability has been recognized as a driver in Leishmania fitness gain in response to environmental change or chemotherapy. How genome instability generates beneficial phenotypes despite potential deleterious gene dosage effects is unknown. Here we address this important open question applying experimental evolution and integrative systems approaches on parasites adapting to in vitro culture. Phenotypic analyses of parasites from early and late stages of culture adaptation revealed an important fitness tradeoff, with selection for accelerated growth in promastigote culture (fitness gain) impairing infectivity (fitness costs). Comparative genomics, transcriptomics and proteomics analyses revealed a complex regulatory network associated with parasite fitness gain, with genome instability causing highly reproducible, gene dosage-independent and -dependent changes. Reduction of flagellar transcripts and increase in coding and non-coding RNAs implicated in ribosomal biogenesis and protein translation were not correlated to dosage changes of the corresponding genes, revealing a gene dosage-independent, post-transcriptional mechanism of regulation. In contrast, abundance of gene products implicated in post-transcriptional regulation itself correlated to corresponding gene dosage changes. Thus, RNA abundance during parasite adaptation is controled by direct and indirect gene dosage changes. We correlated differential expression of small nucleolar RNAs (snoRNAs) with changes in rRNA modification, providing first evidence that Leishmania fitness gain in culture may be controlled by post-transcriptional and epitranscriptomic regulation. Our findings propose a novel model for Leishmania fitness gain in culture, where differential regulation of mRNA stability and the generation of modified ribosomes may potentially filter deleterious from beneficial gene dosage effects and provide proteomic robustness to genetically heterogenous, adapting parasite populations. This model challenges the current, genome-centric approach to Leishmania epidemiology and identifies the Leishmania transcriptome and non-coding small RNome as potential novel sources for the discovery of biomarkers that may be associated with parasite phenotypic adaptation in clinical settings.
650    _2
$a regulace genové exprese $7 D005786
650    _2
$a nestabilita genomu $7 D042822
650    _2
$a lidé $7 D006801
650    12
$a Leishmania donovani $x genetika $7 D007893
650    12
$a leishmanióza viscerální $x parazitologie $7 D007898
650    _2
$a proteomika $7 D040901
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Rajan, K Shanmugha $u The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
700    1_
$a Bussotti, Giovanni $u Institut Pasteur, Université de Paris, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France $u Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, Paris, France
700    1_
$a Varet, Hugo $u Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, Paris, France $u Institut Pasteur, Biomics, Paris, France; Institut Pasteur, UTechS MSBio, Paris, France
700    1_
$a Legendre, Rachel $u Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, Paris, France $u Institut Pasteur, Biomics, Paris, France; Institut Pasteur, UTechS MSBio, Paris, France
700    1_
$a Proux, Caroline $u Institut Pasteur, Biomics, Paris, France; Institut Pasteur, UTechS MSBio, Paris, France
700    1_
$a Douché, Thibaut $u Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, Paris, France
700    1_
$a Giai-Gianetto, Quentin $u Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, Paris, France $u Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, Paris, France
700    1_
$a Chaze, Thibault $u Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, Paris, France
700    1_
$a Cokelaer, Thomas $u Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, Paris, France $u Institut Pasteur, Biomics, Paris, France; Institut Pasteur, UTechS MSBio, Paris, France
700    1_
$a Vojtkova, Barbora $u Department of Parasitology, Faculty of Science, Charles University, Prague, Czech Republic
700    1_
$a Gordon-Bar, Nadav $u The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
700    1_
$a Doniger, Tirza $u The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
700    1_
$a Cohen-Chalamish, Smadar $u The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
700    1_
$a Rengaraj, Praveenkumar $u The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
700    1_
$a Besse, Céline $u Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France
700    1_
$a Boland, Anne $u Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France
700    1_
$a Sadlova, Jovana $u Department of Parasitology, Faculty of Science, Charles University, Prague, Czech Republic
700    1_
$a Deleuze, Jean-François $u Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France
700    1_
$a Matondo, Mariette $u Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, Paris, France
700    1_
$a Unger, Ron $u The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
700    1_
$a Volf, Petr $u Department of Parasitology, Faculty of Science, Charles University, Prague, Czech Republic
700    1_
$a Michaeli, Shulamit $u The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel
700    1_
$a Pescher, Pascale $u Institut Pasteur, Université de Paris, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France $1 https://orcid.org/0000000327967855
700    1_
$a Späth, Gerald F $u Institut Pasteur, Université de Paris, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France $1 https://orcid.org/0000000202562029
773    0_
$w MED00008922 $t PLoS pathogens $x 1553-7374 $g Roč. 18, č. 3 (2022), s. e1010375
856    41
$u https://pubmed.ncbi.nlm.nih.gov/35294501 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220720 $b ABA008
991    __
$a 20220804135410 $b ABA008
999    __
$a ok $b bmc $g 1822674 $s 1170417
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2022 $b 18 $c 3 $d e1010375 $e 20220316 $i 1553-7374 $m PLOS pathogens $n PLoS Pathog $x MED00008922
LZP    __
$a Pubmed-20220720

Find record

Citation metrics

Loading data ...

Archiving options

Loading data ...