Germano Cecere

Comptes Rendus Biologies (CRBIOL)

Comptes RendusBiologiesGermano CecereEpigenetic and gene regulatory functions of small RNAsVolume 346, Special Issue S2 (2023), p. 75-77Online since: 19 December 2023Issue date: 29 March 2024Part of Special Issue: A tribute to François Gros, a founding father of molecularbiologyGuest editors: Margaret Buckingham (Professeur émérite et directeur honoraire dudépartement Biologie du développement et cellules souches à l’Institut Pasteur -Membre de l’Académie des sciences) and Moshe Yaniv (Professeur honoraire àl’Institut Pasteur - Directeur de recherche émérite au CNRS - Membre de l’Académiedes sciences)https://doi.org/10.5802/crbiol.131This article is licensed under theCreative Commons Attribution 4.0 International License.http://creativecommons.org/licenses/by/4.0/C EN T R EMER S ENN EThe Comptes Rendus. Biologies are a member of theMersenne Center for open scientific publishingwww.centre-mersenne.org — e-ISSN : 1768-3238Comptes RendusBiologies2023, Vol. 346, Special Issue S2, p. 75-77https://doi.org/10.5802/crbiol.131A tribute to François Gros, a founding father of molecular biologyEpigenetic and gene regulatory functions of smallRNAsGermano Cecere ,aa Department of Developmental and Stem Cell Biology, Institut Pasteur, UniversitéParis Cité, CNRS UMR3738, Mechanisms of Epigenetic Inheritance, Paris, FranceE-mail: germano.cecere@pasteur.frAbstract. In this review article, I summarize the intervention I made during the “Hommage à FrançoisGros” held at the Institut Pasteur in Paris on the 25th of April, 2023. I discuss how the discoveryof the existence of an RNA intermediate between genetic information and protein translation haschanged our perspective on the role of RNA in gene regulation in these past years. I also discuss newemerging paradigms, highlighting the role of RNA in heritable information similar to the well-knownDNA function.Keywords. Epigenetics, Small RNAs, Gene regulation, RNA.Note. This article follows a symposium held on 25 April 2023 at the Institut Pasteur in tribute toFrançois Gros.Published online: 19 December 2023, Issue date: 29 March 2024In a seminal review article published in 1961,François Jacob and Jacques Monod introduced agroundbreaking concept: the existence of an inter-mediary molecule that bridges the gap between pro-tein synthesis and genetic information [1]. Termedthe “structural messenger”, this hypothetical mole-cule spurred intense speculation within the scien-tific community. Within the same year of the re-view’s publication, François Gros, working in col-laboration with James Watson’s laboratory at Har-vard University, embarked on a quest to decipher theelusive mediator connecting genes to ribosomes [2].Concurrently, Sidney Brenner and François Jacob, inMatthew Meselson’s laboratory at Caltech, embarkedon a parallel journey [3]. Through rigorous experi-mentation, both teams converged on a groundbreak-ing revelation: an RNA molecule, characterized byits instability, emerged as the long-sought interme-diary. This pivotal molecule, named messenger RNA(mRNA), served as the conduit through which ge-netic information was conveyed from DNA to ribo-somes for protein synthesis.This discovery of mRNA heralded a new era inmolecular biology and unveiled RNA’s multifacetedroles in gene regulation. No longer a passive mes-senger, RNA emerged as a central player in orches-trating mRNA synthesis and protein production. In1993, a pivotal discovery occurred in Victor Am-bros’s laboratory. A gene whose mRNA product pro-duced a novel RNA species measuring about 22 nu-cleotides, known as microRNA (miRNA), was un-veiled [4]. This miRNA possessed the remarkableability to modulate the protein expression of othergenes by base-pairing to the end of target mRNAmolecules [4, 5]. Initially discovered in the nematodeCaenorhabditis elegans, miRNAs were later identi-fied in diverse animal models, including humans [6].They emerged as global regulators of gene expressionand play vital roles during development and diseaseprogression [7].Interestingly, the realm of small regulatory RNAsextended beyond the animal kingdom. Viruses thatinfect animal cells harness the potential of these reg-ulatory mechanisms. Viral miRNAs manipulate theISSN (electronic) : 1768-3238 https://comptes-rendus.academie-sciences.fr/biologies/76 Germano Cecerehost’s miRNA machinery, facilitating viral replica-tion by modulating host gene expression [8]. TheCOVID-19 pandemic provided a unique context forinvestigating viral miRNAs in SARS-CoV-2 infection.Our research team revealed the existence of a SARS-CoV-2-derived miRNA that dampened human im-mune responses by downregulating mRNAs involvedin interferon-mediated responses, shedding light onthe intricate interplay between viral infection andhost defense [9].Besides their post-transcriptional regulatory func-tion, small RNAs can also control the RNA synthesisof targeted genomic regions in the nucleus. A classof small regulatory RNAs, known as PIWI-interactingRNAs (piRNAs), has emerged as a conserved RNA-based immune system safeguarding the genome’s in-tegrity against nucleic acid parasites [10]. Primar-ily expressed in the animal germline, piRNAs playa central role in controlling invasive genomic ele-ments such as viruses and transposons. Distinc-tively, piRNAs repress these elements in the nu-cleus at the chromatin level, underscoring their roleas genome guardians. Recent findings from ourteam unveiled an intriguing dimension of piRNAs—beyond defense. We discovered global transcrip-tional repression by piRNAs of endogenous tran-scriptional programs [11]. This repressive function ofpiRNAs is essential for proper gamete differentiationand function. Thus, piRNAs can also repress endoge-nous genes during animal development, highlightingtheir dual role in genome defense and developmen-tal processes.In retrospect, the journey from the postulated“structural messenger” to the intricate web of smallregulatory RNAs exemplifies the evolutionary trajec-tory of our understanding. From mRNA’s pivotalrole in gene expression control to the discovery ofmiRNAs and piRNAs, RNA’s versatility and regulatoryprowess have come to the fore.Recent years have witnessed the emergence of anew paradigm—an insight that shatters the bound-aries that once constrained RNA’s scope. While RNA’srenown rests in its role as a messenger that bridgesgenes to ribosomes, it now claims its place as acornerstone in the realm of heritable information—akin to the role of DNA. The revelation that smallRNAs traverse generations through gametes, impart-ing hereditary traits, has etched a new trajectoryin biology and genetics [12]. Pioneering work inC. elegans illuminated how small RNAs can perpet-uate gene silencing across generations [13, 14]. Re-search from our team has also contributed to this no-tion, revealing the heritable function of small RNAs inembryonic development and animal fertility [15, 16].These heritable RNAs not only influence trait inher-itance but can also shape animal evolution in re-sponse to environmental changes. These tantaliz-ing glimpses into RNA’s uncharted role as a bearer ofheredity underscore the astonishing adaptability in-herent within this once-underestimated molecule.The revelation of heritable RNA has unraveledyet a novel function that RNA holds, promising toreshape our understanding of biology and chart acourse for discoveries yet to come.Declaration of interestsThe authors do not work for, advise, own shares in, orreceive funds from any organization that could bene-fit from this article, and have declared no affiliationsother than their research organizations.References[1] F. Jacob, J. Monod, “Genetic regulatory mechanisms in thesynthesis of proteins”, J. Mol. Biol. 3 (1961), p. 318-356.[2] F. Gros, H. Hiatt, W. Gilbert, C. G. Kurland, R. W. Risebrough,J. D. Watson, “Unstable ribonucleic acid revealed by pulselabelling of Escherichia Coli”, Nature 190 (1961), p. 581-585.[3] S. Brenner, F. Jacob, M. Meselson, “An unstable intermediatecarrying information from genes to ribosomes for proteinsynthesis”, Nature 190 (1961), p. 576-581.[4] R. C. Lee, R. L. Feinbaum, V. Ambros, “The C. elegans hete-rochronic gene lin-4 encodes small RNAs with antisense com-plementarity to lin-14”, Cell 75 (1993), p. 843-854.[5] B. Wightman, I. Ha, G. Ruvkun, “Posttranscriptional regula-tion of the heterochronic gene lin-14 by lin-4 mediates tem-poral pattern formation in C. elegans”, Cell 75 (1993), p. 855-862.[6] A. E. Pasquinelli, B. J. Reinhart, F. Slack, M. Q. Martindale,M. I. Kuroda, B. Maller, D. C. Hayward, E. E. Ball, B. Deg-nan, P. Müller, J. Spring, A. Srinivasan, M. Fishman, J. Finnerty,J. Corbo, M. Levine, P. Leahy, E. Davidson, G. Ruvkun, “Con-servation of the sequence and temporal expression of let-7heterochronic regulatory RNA”, Nature 408 (2000), p. 86-89.[7] D. P. Bartel, “Metazoan MicroRNAs”, Cell 173 (2018), p. 20-51.[8] S. Pfeffer, M. Zavolan, F. A. Grässer, M. Chien, J. J. Russo, J. Ju,B. John, A. J. Enright, D. Marks, C. Sander, T. Tuschl, “Iden-tification of virus-encoded MicroRNAs”, Science 304 (2004),p. 734-736.[9] M. Singh, M. Chazal, P. Quarato, L. Bourdon, C. Malabat,T. Vallet, M. Vignuzzi, S. van der Werf, S. Behillil, F. Donati,Germano Cecere 77N. Sauvonnet, G. Nigro, M. Bourgine, N. Jouvenet, G. Cecere,“A virus-derived microRNA targets immune response genesduring SARS-CoV-2 infection”, Embo Rep. 23 (2022), articleno. e54341.[10] D. M. Ozata, I. Gainetdinov, A. Zoch, D. O’Carroll, P. D.Zamore, “PIWI-interacting RNAs: small RNAs with big func-tions”, Nat. Rev. Genet. 20 (2019), p. 89-108.[11] E. Cornes, L. Bourdon, M. Singh, F. Mueller, P. Quarato,E. Wernersson, M. Bienko, B. Li, G. Cecere, “piRNAs initiatetranscriptional silencing of spermatogenic genes during C. el-egans germline development”, Dev. Cell. 57 (2022), p. 180-196,e1–e7.[12] G. Cecere, “Small RNAs in epigenetic inheritance: from mech-anisms to trait transmission”, Febs Lett. 595 (2021), p. 2953-2977.[13] A. Fire, S. Xu, M. K. Montgomery, S. A. Kostas, S. E. Driver, C. C.Mello, “Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans”, Nature 391 (1998),p. 806-811.[14] A. Grishok, H. Tabara, C. C. Mello, “Genetic requirements forinheritance of RNAi in C. elegans”, Science 287 (2000), p. 2494-2497.[15] P. Quarato, M. Singh, E. Cornes, B. Li, L. Bourdon, F. Mueller,C. Didier, G. Cecere, “Germline inherited small RNAs facilitatethe clearance of untranslated maternal mRNAs in C. elegansembryos”, Nat. Commun. 12 (2021), article no. 1441.[16] G. Barucci, E. Cornes, M. Singh, B. Li, M. Ugolini, A. Samolygo,C. Didier, F. Dingli, D. Loew, P. Quarato, G. Cecere, “Small-RNA-mediated transgenerational silencing of histone genesimpairs fertility in piRNA mutants”, Nat. Cell Biol. 22 (2020),p. 235-245.

Epigenetic and gene regulatory functions of small RNAs

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Epigenetic and gene regulatory functions of small RNAs

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