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\DOI{10.5802/crbiol.131}
\datereceived{2023-09-27}
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\dateposted{2023-12-19}
\datepublished{2024-03-29}
\begin{document}

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%\makeatletter
%\def\TITREspecial{\relax}
%\def\cdr@specialtitle@english{A tribute to Fran\c{c}ois Gros, a founding father of molecular biology}
%\def\cdr@specialtitle@french{Un hommage \`a Fran\c{c}ois Gros, un des p\`eres de la biologie mol\'eculaire}
%\makeatother

\title{Epigenetic and gene regulatory functions of small RNAs}

\alttitle{Fonctions \'{e}pig\'{e}n\'{e}tiques et de r\'{e}gulation g\'{e}nique des petits ARN}

\author{\firstname{Germano} \lastname{Cecere}\CDRorcid{0000-0001-5912-3417}}
\address{Department of Developmental and Stem Cell Biology, 
Institut Pasteur, Universit\'{e} Paris Cit\'{e}, CNRS UMR3738, 
Mechanisms of Epigenetic Inheritance, Paris, France}
\email{germano.cecere@pasteur.fr}

\keywords{\kwd{Epigenetics} \kwd{Small RNAs} \kwd{Gene regulation} \kwd{RNA}}

\altkeywords{\kwd{\'{E}pig\'{e}n\'{e}tique} \kwd{Petits ARNs} \kwd{R\'{e}gulation des g\`{e}nes} \kwd{RNA}}

\def\thanksname{Note}
\thanks{This article follows a symposium held on 25 April 2023 at the
Institut Pasteur in tribute to Fran\c{c}ois Gros.}

\begin{abstract}
In this review article, I summarize the intervention I made during the
``Hommage \`{a} Fran\c{c}ois Gros'' held at the Institut Pasteur in
Paris on the 25th of April, 2023. I discuss how the discovery of the
existence of an RNA intermediate between genetic information and
protein translation has changed our perspective on the role of RNA in
gene regulation in these past years. I also discuss new emerging
paradigms, highlighting the role of RNA in heritable information
similar to the well-known DNA function.
\end{abstract}

\begin{altabstract}
Dans cet article de synth\`{e}se, je r\'{e}sume l'intervention que j'ai
faite lors du colloque \guillemotleft{}~Hommage \`{a} Fran\c{c}ois
Gros~\guillemotright{} qui s'est tenu le 25 avril 2023 \`{a} l'Institut
Pasteur \`{a} Paris. J'explique comment la d\'{e}couverte de
l'existence d'un ARN interm\'{e}diaire entre l'information
g\'{e}n\'{e}tique et la traduction des prot\'{e}ines a chang\'{e} notre
perspective sur le r\^{o}le de l'ARN dans la r\'{e}gulation des
g\`{e}nes au cours de ces derni\`{e}res ann\'{e}es. Je discute
\'{e}galement de nouveaux paradigmes \'{e}mergents, en soulignant le
r\^{o}le de l'ARN dans la transmission d'informations
h\'{e}r\'{e}ditaires, analogue \`{a} la fonction bien connue de l'ADN.
\end{altabstract}

\maketitle

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\xsection{}
In a seminal review article published in 1961, Fran\c{c}ois Jacob and
Jacques Monod introduced a groundbreaking concept: the existence of an
intermediary molecule that bridges the gap between protein synthesis
and genetic information~\cite{1}.  Termed the ``structural messenger'',
this hypothetical molecule spurred intense speculation within the
scientific community. Within the same year of the review's publication,
Fran\c{c}ois Gros, working in collaboration with James Watson's
laboratory at Harvard University, embarked on a quest to decipher the
elusive mediator connecting genes to  ribosomes~\cite{2}. Concurrently,
Sidney Brenner and Fran\c{c}ois Jacob, in Matthew Meselson's laboratory
at Caltech, embarked on a parallel  journey~\cite{3}. Through rigorous
experimentation, both teams converged on a groundbreaking revelation:
an RNA molecule, characterized by its instability, emerged as 
the long-sought
intermediary. This pivotal molecule, named messenger RNA
(mRNA), served as the conduit through which genetic information was
conveyed from DNA to ribosomes for protein synthesis.

This discovery of mRNA heralded a new era in molecular biology and
unveiled RNA's multifaceted roles in gene regulation. No longer a
passive messenger, RNA emerged as a central player in orchestrating
mRNA synthesis and protein production. In 1993, a pivotal discovery
occurred in Victor Ambros's laboratory. A gene whose mRNA product
produced a novel RNA species measuring about 22 nucleotides, known as
microRNA (miRNA), was  unveiled~\cite{4}. This miRNA possessed the
remarkable ability to modulate the protein expression of other genes by
base-pairing to the end of target mRNA molecules~\cite{4,5a}. Initially discovered
in the nematode \textit{Caenorhabditis elegans}, miRNAs were later
identified in diverse animal models, including humans~\cite{6a}. They emerged as
global
regulators of gene expression and play vital roles 
during development and disease\unskip\break    
progression~\cite{5}.

Interestingly, the realm of small regulatory RNAs extended beyond the
animal kingdom. Viruses that infect animal cells harness the potential
of these regulatory mechanisms. Viral miRNAs manipulate the host's
miRNA machinery, facilitating viral replication by modulating host gene
expression~\cite{6}.  The COVID-19 pandemic provided a unique context
for investigating viral miRNAs in SARS-CoV-2 infection. Our research
team revealed the existence of a SARS-CoV-2-derived miRNA that dampened
human immune responses by downregulating mRNAs involved in
interferon-mediated responses, shedding light on the intricate
interplay between viral infection and host  defense~\cite{7}.

Besides their post-transcriptional regulatory function, small RNAs can
also control the RNA synthesis of targeted genomic regions in the
nucleus. A class of small regulatory RNAs, known as PIWI-interacting
RNAs (piRNAs), has emerged as a conserved RNA-based immune system
safeguarding the genome's integrity against nucleic acid 
parasites~\cite{8}. Primarily expressed in the animal germline, piRNAs
play a central role in controlling invasive genomic elements such as
viruses and transposons. Distinctively, piRNAs repress these elements
in the nucleus at the chromatin level, underscoring their role as
genome guardians. Recent findings from our team unveiled an intriguing
dimension of piRNAs---beyond defense. We discovered global
transcriptional repression by piRNAs of endogenous transcriptional 
programs~\cite{9}. This repressive function of piRNAs is essential for
proper gamete differentiation and function. Thus, piRNAs can also
repress endogenous genes during animal development, highlighting their
dual role in genome defense and developmental processes.

In retrospect, the journey from the postulated  ``structural
messenger'' to the intricate web of small regulatory RNAs exemplifies
the evolutionary trajectory of our understanding. From mRNA's pivotal
role in gene expression control to the discovery of miRNAs and piRNAs,
RNA's versatility and regulatory prowess have come to the fore.

Recent years have witnessed the emergence of a new  paradigm---an
insight that shatters the boundaries that once constrained RNA's scope.
While RNA's renown rests in its role as a messenger that bridges genes
to ribosomes, it now claims its place as a cornerstone in the realm of
heritable information---akin to the role of DNA. The revelation that
small RNAs traverse generations through gametes, imparting hereditary
traits, has etched a new trajectory in biology and genetics~\cite{10}.
Pioneering work in\break \textit{C. elegans} illuminated how small RNAs can
perpetuate gene silencing across  generations~\cite{11,12}.  Research
from our team has also contributed to this notion, revealing the
heritable function of small RNAs in embryonic development and animal 
fertility~\cite{13,14}. These heritable RNAs not only influence trait
inheritance but can also shape animal evolution in response to
environmental changes. These tantalizing glimpses into RNA's uncharted
role as a bearer of heredity underscore the astonishing adaptability
inherent within this once-underestimated molecule.

The revelation of heritable RNA has unraveled yet a novel function that
RNA holds, promising to reshape our understanding of biology and chart
a course for discoveries yet to come.

\section*{Declaration of interests}
The authors do not work for, advise, own shares in, or receive funds
from any organization that could benefit from this article, and have
declared no affiliations other than their research organizations.

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