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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Serie: ISTE Invoiced
- Sprache: Englisch
Genetics and its mysterious little sister, epigenetics, have deep roots in the history of biology. Today, epigenetics is of paramount importance in not only the fundamental sciences, but also in life science applications, ranging from molecular biology, and disease diagnosis and treatment, to agriculture.
Epigenetics in Ecology and Evolution traces the history of the concept of epigenetics in biology and describes the molecular mechanisms concerned. It examines the contributions that the emerging discipline of epigenetics has made to the fields of ecology and evolution, regarding both plant and animal organisms, as well as its place in our society.
By exploring the importance of epigenetics at varying levels, from the cell to the organism as a whole, and even to the ecosystem, this book offers answers that are accessible to a wide audience, from scientifically curious citizens to students and professionals working in the world of biology. The aim is to enable everyone to acquire or develop a critical and informed perspective on the complex relationships between genetics and epigenetics.
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Veröffentlichungsjahr: 2025
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Table of Contents
Cover
Table of Contents
Title Page
Copyright Page
Preface
1 A Brief Conceptual History of Epigenetics, and More Besides
1.1. Introduction
1.2. The birth of the term: from epigenesis to pangenesis
1.3. From pangene to classical gene
1.4. Classical epigenetics
1.5. Molecular epigenetics
1.6. Epigenetics without knowing it, or Mr. Jourdain’s epigenetics
1.7. Post-genomic epigenetics: epigenomics
1.8. Developmental, ecological and evolutionary epigenetics
1.9. Epigenetics and ethics
1.10. Conclusion
1.11. References
2 Molecular Players of Epigenetic Information
2.1. Introduction
2.2. DNA methylation
2.3. Histone modifications
2.4. Chromatin topology
2.5. Regulatory RNAs
2.6. Conclusion
2.7. References
3 Epigenetics and Transposable Elements
3.1. Introduction
3.2. TEs in genomes
3.3. Impact of TEs on phenotype
3.4. The effect of TE in adaptation and evolution
3.5. Conclusion
3.6. References
4 Epigenetics: The Same for all Species?
4.1. Universal epigenetic mechanisms?
4.2. Origin of the various chromatin components
4.3. Evolution of epigenetic systems
4.4. Example of the evolution of DNA methylation in different groups of organisms
4.5. Which model organisms for epigenetics?
4.6. References
5 Epigenome Modifications as a Therapeutic and Research Tool
5.1. Introduction
5.2. Epigenetic modification strategies
5.3. Epigenetic modification targeting DNA methylation
5.4. Epigenetic modification of histone epigenetic marks
5.5. dCas9-based technology to edit nuclear architecture
5.6. dCas9 fused to transcription factors
5.7. dCas13-based technology to edit RNA modifications
5.8. Conclusion
5.9. References
6 Epigenetics and Stress
6.1. Impact of environmental constraints on epigenetic marks in animals and humans
6.2. Impact of environmental stress on epigenetic marks in plants
6.3. Conclusion
6.4. References
7 Phenotypic Plasticity, Epigenetics and Adaptability
7.1. Introduction
7.2. Experimental approach to PP
7.3. Molecular mechanisms of PP
7.4. Evolution of PP
7.5. Evolution through PP
7.6. Conclusion
7.7. References
8 Epigenetics and Climate Change: The Example of Forest Ecosystems
8.1. Introduction: an ecological crisis on an unprecedented scale
8.2. Forests and climate change: from current situation to challenges
8.3. Epigenetics as a source of flexibility in trees in a context of GC
8.4. Conclusion
8.5. Acknowledgements
8.6. References
9 Epigenetics and Crop Improvement
9.1. Introduction
9.2. Defining agricultural transition objectives and challenges
9.3. The contribution of (epi)genetics to the definition of traits of agronomic interest and the construction of ideotypes
9.4. The role of epigenetics in current selection schemes
9.5. The final stages before a new variety is labeled
9.6. Development of new varieties without sexual crossing
9.7. Legislation and marketing of varietal innovations resulting from epigenetic variations
9.8. Conclusion and prospects
9.9. References
10 Epigenetics and Livestock Improvement
10.1. Introduction
10.2. Genetic selection issues and epigenetic improvement levers
10.3. Early phenotype programming
10.4. Transgenerational epigenetic effects
10.5. Conclusion
10.6. References
11 Epigenetics in Evolution
11.1. Evolution, Environments and Inheritance
11.2. Conclusions and further readings
11.3 References
12 Epigenetics and Society: Epigenetics in the French Press
12.1. Introduction
12.2. Data and methodology
12.3. Epigenetics press
12.4. Words and categories
12.5. A look at epigenetics in the French press
12.6. Discussion: the appeal and visibility of epigenetics
12.7. Conclusion
12.8. References
List of Authors
Index
End User License Agreement
List of Tables
Chapter 8
Table 8.1. Summary of the main ecosystem services provided by forests. Accordi...
Chapter 12
Table 12.1. Lexical terms (on a color scale from white to green, the lowest ne...
List of Illustrations
Chapter 1
Figure 1.1. Epigenetics has many faces. Its definition depends on the context ...
Figure 1.2(A). Google Ngram representing the evolution of the frequency (in lo...
Figure 1.2(B). Google Ngram representing the evolution of the frequency (in lo...
Figure 1.3. The central dogma of molecular biology, in its contemporary versio...
Figure 1.4. The reinterpretation of Weismannism (a) in terms of the central do...
Figure 1.5. Terminological linkages of epigenetics
Chapter 2
Figure 2.1. Epigenetic information is physically stored in several types of mo...
Figure 2.2. DNA methylation. a) Principle of DNA methylation by DNMTs and deme...
Figure 2.3. Histone modifications and their functions....
Figure 2.4. Chromatin topology. The different levels of chromosome folding in ...
Figure 2.5. TAD function. Chromatin interactions are favored within TADs, nota...
Figure 2.6. PTGS (Post-Transcriptional Gene Silencing) and TGS (Transcriptiona...
Figure 2.7. Model of transcriptional repression involving regulatory RNAs in t...
Figure 2.8. Production and action pathways of hcsiRNAs in plants. The RdDM (RN...
Chapter 3
Figure 3.1. Classification of transposable elements Classification des élément...
Figure 3.2. Ratio of the most common types of transposable elements in eukaryo...
Figure 3.3. Comparison of chromosome repeat density between Arabidopsis thalia...
Figure 3.4. Effects of TEs by insertion site
Figure 3.5. Genetic and epigenetic effect of a TE on gene transcription: the e...
Chapter 4
Figure 4.1. Distribution of methylation in genes (A) and repeat regions (B), f...
Chapter 5
Figure 5.1. Allosteric versus catalytic enzyme inhibitor
Figure 5.2. Disruption of the SARS-CoV2-ACE2 receptor interaction by the PPI d...
Figure 5.3. Epigenetic ligands modulate gene expression
Figure 5.4. Cas 9 enzyme from Streptococcus pyogenes that cuts three nucleotid...
Figure 5.5. Cas9 enzyme is engineered by two mutations in the RuvC and NHN dom...
Figure 5.6. The gene expression process starts with DNA transcription into RNA...
Figure 5.7. Different systems to attach epigenetic effectors to a targeted seq...
Figure 5.8. Test environments and transfection methods to deliver nucleic acid...
Figure 5.9. Examples of DNMT inhibitors
Figure 5.10. Examples of TET inhibitors
Figure 5.11. Agouti viable yellow (Avy) coat color in mice is associated with ...
Figure 5.12. Epigenetic enzymes that modify histone modifications to activate ...
Figure 5.13. CRISPR-PIN and CRISPR-GO systems for targeting genomic loci to th...
Figure 5.14. Addition of plant hormone abscisic acid (ABA) represented by the ...
Chapter 6
Figure 6.1. Epigenetic modulation of the HPA axis and reactivity to stress (cr...
Figure 6.2. Epigenetic clock.
Figure 6.3. Photoperiod, epigenetics and flowering.
Figure 6.4. Temperature, epigenetics and flowering.
Figure 6.5. Flowering and epigenetic marks of the FWA locus. When the plant is...
Figure 6.6. Epigenetics and response to a viral infection.
Figure 6.7. Memory of viral attacks. Viral RNAs will initiate the production o...
Figure 6.8. Epigenetics and acquired resistance. The insertion of a DNA fragme...
Chapter 7
Figure 7.1. The “epigenetic landscape” imagined by C. Waddington (see Chapter ...
Figure 7.2. Schematic representation of the reaction norm and some examples of...
Chapter 8
Figure 8.1. We are living in an era of great environmental change. Could epige...
Figure 8.2. The role of phenotypic plasticity and genetic evolution of a trait...
Figure 8.3. Example of phenotypic plasticity in two tree traits: A) Anatomical...
Figure 8.4. Illustration of a beech tree’s “crown decline” following a gas emb...
Figure 8.5. Two scales for studying epigenetic variability in forest trees: in...
Figure 8.6. Illustration of the temporal causal chain of reception of an envir...
Figure 8.7. Epigenetic mechanisms (here, an illustration of the effects of DNA...
Figure 8.8. Exploiting epigenetic diversity in the production of forest reprod...
Chapter 9
Figure 9.1. New challenges in plant breeding, where epigenetics (represented b...
Figure 9.2. Comparative diagram of conventional breeding of new rice varieties...
Figure 9.3. Hypothetical epibreeding strategy to improve crop resilience to cl...
Chapter 10
Figure 10.1. Interaction between genetics, epigenetics and environment in the ...
Figure 10.2. Epigenetic mechanisms of thermal heat conditioning in birds. Crea...
Chapter 11
Figure 11.1. In these two examples of phenotypic variability, two types of ada...
Figure 11.2. Relations between the duration of environmental change, response ...
Chapter 12
Figure 12.1. Correspondence factor analysis (CFA) of classes produced by desce...
Guide
Cover Page
Table of Contents
Title Page
Copyright Page
Preface
Begin Reading
List of Authors
Index
Wiley End User License Agreement
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SCIENCES
Ecosystems and EnvironmentField Directors – Françoise Gaill and Dominique Joly
Epigenetics, Subject Head – Dominique Joly
Epigenetics in Ecology and Evolution
Coordinated by
Christoph Grunau
Stéphane Maury
First published 2025 in Great Britain and the United States by ISTE Ltd and John Wiley & Sons, Inc.
Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA. Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address:
ISTE Ltd27-37 St George’s RoadLondon SW19 4EUUKwww.iste.co.uk
John Wiley & Sons, Inc.111 River StreetHoboken, NJ 07030USAwww.wiley.com
© ISTE Ltd 2025The rights of Christoph Grunau and Stéphane Maury to be identified as the authors of this work have been asserted by them in accordance with the Copyright, Designs and Patents Act 1988.
Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s), contributor(s) or editor(s) and do not necessarily reflect the views of ISTE Group.
Library of Congress Control Number: 2025931324
British Library Cataloguing-in-Publication DataA CIP record for this book is available from the British LibraryISBN 978-1-78945-216-7
ERC code:LS2 Integrative Biology: from Genes and Genomes to Systems LS2_3 EpigeneticsLS8 Environmental Biology, Ecology and Evolution LS8_6 Evolutionary ecology LS8_7 Evolutionary genetics
Preface
Christoph GRUNAU1 and Stéphane MAURY2
1 IHPE, Université de Perpignan Via Domitia, France
2 P2E, Université d’Orléans, France
Genetics and its mysterious little sister, epigenetics, have deep roots in the history of biology. After embryology’s revival in the modern era, in which preformationist visions of development and epigenesis clashed, the latter triumphed in the 19th century, with the heredity of acquired traits being accepted. In the latter part of the 19th century, the notion of stable inheritance of characters through generations emerged, a notion inherited by the “classic” concept of the gene in the early 20th century. Genetics now focuses on the transmission of traits between generations, putting aside generation itself (in the sense of the genesis of a living being). Epigenetics has grown in this “all-genetic” context. First defined as the study of the links between genotype and phenotype by Conrad Waddington in the 1940s, epigenetics was redefined a few years later by David L. Nanney, during the emergence of molecular biology, as the set of factors that modulate gene function in a heritable way without changing the DNA sequence.
Today, the concept of epigenetics is important in a wide variety of fields ranging from molecular biology to disease diagnosis and treatment, as well as covering the improvement of animal and plant species for agricultural use, as well as the relationships between species, biodiversity and evolution. Business models based on the use of epigenetic markers and concepts are beginning to emerge, raising questions of public awareness and perception. Epigenetics remains a complex field, which is sometimes still enigmatic or misunderstood in certain situations, and not only by the general public.
This book attempts to provide answers to as wide an audience as possible, enabling readers to build or consolidate a critical and enlightened view of the complex relationships between genetics and epigenetics.
Lastly, the editors and authors would like to express their gratitude to the organizations that generously supported the writing of this handbook. Their contribution was essential in making this work possible: the CNRS, the GDR3E (Epigenetics, Ecology and Evolution), the Labex CeMEB (ANR-10-LABX-04-01) and the public library of Collioure (France).
February 2025
1A Brief Conceptual History of Epigenetics, and More Besides
Arnaud POCHEVILLE
CRBE, Université de Toulouse, France
1.1. Introduction
Epigenetics concerns the expression of genetic information – or, more generally, non-genetic (biological) information altogether.
A polymorphous concept with multiple origins, sometimes used very liberally or absent where it is expected, epigenetics is deeply rooted in understanding “generation”, in other words, the way in which living beings are formed.
There are two main groups of answers to the question of generation: either the form is already there, pre-existing its manifestation in the organized being; or it is created as it grows.
The history of epigenetics is the history of a dialectic between these two groups, always in tension, always on the verge of resolution, always in transformation.
Figure 1.1.Epigenetics has many faces. Its definition depends on the context in which we find ourselves, and it may yet evolve. Follow us in Chapter 1 to find out why. Illustration by Annette Köhn
1.2. The birth of the term: from epigenesis to pangenesis
The term “epigenetics“appeared in the 17th century as a noun, “epigenesis”, in a treatise by the English physician and anatomist William Harvey (1651, Exercitatio 45). In it, Harvey outlined his work on the causes of animal generation, responding in particular to Aristotle (330–322 BCE) (Aristotle 1887) and his own master, Fabricius (1621). Harvey distinguishes two possible modes of generation: either the material of the future animal is already present and receives its form like wax imprinted by a seal, all parts being formed simultaneously, which he calls metamorphosis; or the material is added as the form is born, like a potter’s pot, the parts of the animal coming into being from one another, which he calls epigenesis. For Harvey, the generation of the chick from the egg is clearly the result of epigenesis, not metamorphosis. It is an idea that is tempting to see already discussed, albeit ambiguously, by Aristotle; however, it is important to bear in mind the differences in frameworks and debates between eras (Lennox 2006; Goy 2018; Bolduc 2021).
In the 18th century, another vision of generation gained ground: mechanistic preformationism (Bowler 2001, pp. 26–28). Preformationism assumes that form pre-exists generation. From an empirical point of view, the idea is justified by the observation (thanks to the use of the microscope) of microscopic organs and organisms, which suggest the possible existence in the living world of structures of infinitesimal size and therefore undetectable to our senses (Malpighi 1666; Malebranche 1674, pp. 41–42; see Gasking 1967, pp. 45–46, quoted by Roe 1981, pp. 83–87). From a philosophical point of view, preformation allows the formation of a living being to be reduced to simple growth, a mechanism set in motion at conception, at a time when the mechanistic vision is gaining traction (Bowler 2001, pp. 26–28; Wolfe 2016, 2017). The most extreme form of this vision (known as pre-existing germs) assumes that all living beings pre-exist their generation, nested like nesting dolls within each other since Creation, such as aphids whose parthenogenesis and nested generations are demonstrated by a proponent of preformation (Bonnet 1745, 1762, Chapter 1, 1770, pp. 190–191). This vision resonates with a Christian point of view, which in turn justifies the comprehensibility of the world (God lays down natural laws) (Roe 1981, p. 111; Bowler 2001, pp. 29–31). Conversely, preformationists see epigenesis as synonymous with chance, chaos and indeterminacy (and hence incomprehensibility). Advocates of atheism favor epigenetic theories, as well as those of spontaneous generation, which dispense with the idea of Creation (Buffon 1749; see Roe 1981, pp. 16–18; Spallanzani 1765; d’Holbach 1770; Bowler 2001, pp. 29–36).
Mechanistic preformationism fell into disfavor at the turn of the 18th and 19th centuries (Roe 1981, p. 150; Bowler 2001, p. 32; Wolfe 2016, 2017). We would prefer an epigenesis whose mechanistic vision is supplemented by the idea of forces specific to living organisms, which organize them (e.g. Maupertuis 1745, Chapter XI–XII, 1756a, Chapter LXV–LXVII; see Ibrahim 2019; Wolff 1759, 1768; Blumenbach 1780; see Bowler 2001, pp. 40–42; Dupont 2007; Wolfe 2019; Schmitt 2021). This vision gives rise to mystical trends (Naturphilosophie: Schelling 1797; Oken 1809; Bowler 2001, pp. 41–42), as well as to so-called teleomechanist trends, which aim to naturalize the notion of finality in living organisms, embryogenesis appearing to be such a process oriented towards a finality, the formed organism (Kant 1790; Lenoir 1982; Bowler 2001, p. 42; Huneman 2006; Moreno and Mossio 2015). The vision that emerges is that of a homology between the individual and the lineage, with parents shaping their children in the same way a craftsman produces an artifact, in a process akin to copying the parent, part by part – there is therefore, said in today’s terms, inheritance of acquired traits (Bowler 2001, p. 23, 38).
This is a vision carried forward by Jean-Baptiste de Lamarck (1809a, Chapter II)in particular, who produced a veritable physicalist theory of the transformation of living beings (and of their spontaneous generation). For him, living beings become organized and complex throughout life and across generations by virtue of movements of fluids, caused by the use of certain parts of the organism whose needs, according to circumstances, are felt (Lamarck 1809b, Chapter VI). The use of a part strengthens it, and the acquired form is transmitted to descendants: this is a law that Lamarck considers empirically evident – the same one that posterity has associated with the neck of the giraffe (Lamarck 1809a, Chapter VII, p. 235). This posterity, sometimes simplifying and very unfaithful, remained influential until the middle of the 20th century, particularly in France, where it resonated with nationalist impulses that were sporadically reactivated by the international context (Boesiger 1980; Limoges 1980; Sapp 1987, pp. 124–128). However, we must be wary of reducing Lamarck to transformism through the inheritance of acquired traits (Bowler 2001, p. 37; Corsi 2001): his intuitions on the self-organization of what we would today call open systems are more reminiscent of the physics of out-of-equilibrium systems (Nicolis and Prigogine 1977; Bejan and Lorente 2004), and, in biology, organizational approaches to viability (Moreno and Mossio 2015).
In the Germanic world, teleomechanism underwent influential developments, culminating in the formulation of the law of parallelism – in the course of its development, the embryo passed through the hierarchy of animal forms, from fish to reptile to mammal, with man at the top (Meckel 1821, 1828contra Von Baer 1828; Russell 1916; Temkin 1950; Oppenheimer 1967; Bowler 2001, pp. 42–44); a law which, when interpreted as the product of evolutionary history, forms the basis of recapitulation theory – the developing embryo recapitulates its evolutionary history (Haeckel 1866). Recapitulation theory, such as Lamarck’s transformism, invites us to understand the transmission of traits between generations as analogous to memory (Haeckel 1876; Gould 1977; Robinson 1979; Bowler 2001, p. 52). However, teleomechanist embryologists are not so much interested in trait transmission as in how the “potentialities” of a fertilized egg develop (Lenoir 1982, Chapter 3; Bowler 2001, p. 44).
Meanwhile, heredity was emerging as a subject of study in its own right, particularly in the medical field, with the study of hereditary diseases (Lopez-Beltran 2007)1. In the 18th century, the notion of heredity could be prefigured by the study of noble diseases (such as gout), supposedly acquired through lifestyle (delicious food) and transmissible diseases, which resonated with the pressure put on the aristocratic family (Pomata 2003, p. 150; Müller-Wille and Rheinberger 2007, p. 11, 19). Mendelian-looking studies, such as that by Pierre Louis Moreau de Maupertuis (1756b, letter xiv, pp. 275–278) on the prevalence of polydactyly in a Berlin family, were in fact interpreted within a framework of epigenesis with the transmission of acquired traits (Bowler 2001, pp. 33–35; Terrall 2007, pp. 265–268). In the 19th century, the social tropism for the study of hereditary diseases changed (Müller-Wille and Rheinberger 2007, p. 19). Among other things, the aim was to improve hygiene: the poorer classes and their share of diseases, supposedly caused by the environment and being more or less hereditary, were perceived as the new threat to social order (Pomata 2003; Cartron 2007; Müller-Wille and Rheinberger 2007, p. 19). Other fields of study also fed into these reflections, such as animal and plant hybridization experiments (aimed at testing fixism and the possibility of establishing new species, along Linnaeus’ lines), natural history and taxonomy (concerned with the constancy of traits), the maintenance and improvement of plants and animals for breeding and collection (their transport over great distances making it possible to better distinguish the intrinsic characteristics of varieties from the effects of the environment), and anthropology, which studies human diversity, in particular skin color (Müller-Wille and Rheinberger 2007, pp. 19–23). In the 1830s, French physiologists came up with a noun corresponding to the adjective “hereditary”, which had been used to describe certain diseases since Antiquity – a noun that until then had only been used in the legal sphere, and which has now taken root in the study of living organisms: heredity (Lopez-Beltran 2007). With the study of heredity, the point of interest is no longer the material mechanism of reproduction (it would be a matter of understanding how a fellow human being is conceived), but the “transmission” of properties between parents and descendants (e.g. knowing the laws of transmission of hereditary diseases would suffice) (Sapp 1987, Chapter 2; Bowler 2001, p. 129; Müller-Wille and Rheinberger 2007).
Box 1.1.Mendel, a historical digression
At the same time as Darwin was proposing his theory of pangenesis, Gregor Mendel was conducting his now-famous hybridization experiments on peas (Mendel 1866, 1901). Mendel’s work was part of a long line of hybridization experiments aimed at obtaining new horticultural varieties or, with a more theoretical ambition, testing the possibility of creating new species, within a framework inherited from Linné where genera were fixed (Linné 1760; Koelreuter 1761; Gärtner 1849; Olby 1979; Bowler 2001, p. 97). It is within this framework that Mendel distinguishes between constant hybrids (in which traits do not segregate, and which can give rise to new species), and variable hybrids (in which traits segregate, according to precise ratios, with some traits being dominant and others recessive) (Callender 1988). Such phenomena had been observed before, but no one had undertaken a systematic study of trait genealogy across generations (Bowler 2001, p. 99). Mendel never mentions particulate inheritance; his categories, far from being materialistic, instead evoke the philosophy of Aristotle in which he was trained: the notion of trait is reminiscent of essence; the dominant/recessive notions are reminiscent of actual/potential (Kalmus 1983; quoted by Bowler 2001, p. 104). The fact that Mendel was not interested – contrary to what early geneticists claimed – in establishing universal laws of heredity may explain the obscure trajectory of his work (Olby 1979, 1985; Sandler and Sandler 1985; Callender 1988). Indeed, his name seems to have been used by researchers as much as a rhetorical argument (to provide a historical anchor in a priority dispute) as a scientific one (Bowler 2001, pp. 113–116).
The term heredity was borrowed by Charles Darwin and his followers to name the transmission of individual variations in his theory of evolution by natural selection (Darwin 1837, 1838; Spencer 1864, Chapter viii; Keller 2010, p. 21). This theory is based on the notion of hereditary variation, which can either be blind (not directed towards adaptation) or acquired (as in Lamarck). Darwin backs up his theory of evolution with a theory of reproduction, but the latter remains dependent on its century – not to say the previous century: it involves “gemmules“, germs of infinitesimal size that come from all parts of the parent organism and reconstitute these parts in the child organism (Darwin 1865, 1868, Chapter XXVII, p. 375, n. 29; Olby 1963; Bowler 2001, pp. 54–64). Darwin called this the “theory of pangenesis“: from pan, “all”, in Greek. However, it was not the near obsolescence of the pangenesis hypothesis that stood in the way of Darwin’s contemporaries accepting the principle of natural selection, but rather their attachment – even by his most enthusiastic supporters – to a “neo-Lamarckian” vision of evolution, in which selection by blind variation is insufficient to explain living things (Bowler 1983, pp. 27–28; Bowler 2001, pp. 54–64).
1.3. From pangene to classical gene
A fervent reader of Darwin, and nonetheless a good critic, was his cousin Francis Galton (Galton 1871a, 1871b; Bowler 2001, p. 64). From the outset, Galton was wary of pangenesis; he developed a theory of heredity (known as ancestral heredity), which defines the transmission of a particulate material that remains stable through generations: the ancestors of all previous generations participate in the material inherited by an individual, following a geometric progression that ensures that the most recent ancestors contribute the most (Galton 1886, pp. 260–261, 1889, p. 148, 1897 contra Johannsen 1911, p. 138; see Sapp 1987, p. 39; Gayon 1992, p. 138; Bulmer 1998; Bowler 2001, p. 67). This stability of hereditary material represents “hard inheritance”, as opposed to “soft inheritance”, which allows the transmission of acquired traits (Mayr and Provine 1998, p. xi; Bowler 2001, p. 68). Hard heredity introduces a decoupling between the transmission of traits and the generation of individuals. From a methodological point of view, this decoupling enables Galton to forego physiology and approach the question of heredity at a population level through statistics (Bowler 2001, p. 69). Galton’s notion of hard heredity resonated with his social concerns: Galton founded eugenics, a utopian movement which, concerned about the effects of civilization on human beings, aimed to improve them, particularly (but not only) through the selection of their reproducers (Galton 1883, p. 4, 24–25, n. 1; Gayon 1992, pp. 168–180; Bowler 2001, pp. 66, 70–72, Chapter 8; Gayon 2004). This being said, some advocates of soft heredity defended similar programs, while others, supporters of hard heredity, opposed them (Sapp 1987, Chapter 6; Bowler 2001, Chapter 8).
The development of a notion of hard heredity was also nurtured by developments in cytology. Cell theory, which posits the cell as the basic unit of life, developed in the 1830s, nurtured by a teleomechanist view (Lenoir 1982, Chapter 3, Chapter 5), with many biologists accepting it by the 1850s in a crystallized version according to which the cell cannot be formed from non-cellular material – notably in contrast to the pangenesis hypothesis (Bowler 2001, p. 74, 85). Moreover, it seems clear since the discovery of the mammalian ovum (Von Baer 1827) that the embryo grows from a single cell, raising the question of cellular differentiation (Bowler 2001, pp. 78–79). Improved microscopy and new dyeing techniques began to bring attention to the cell nucleus around the 1870s, with work on phenomena such as the fusion of gamete nuclei during fertilization (Hertwig 1875), chromosome migration during mitosis (Flemming 1879; Paweletz 2001) and the reduction in number of chromosomes during meiosis (Van Beneden 1883), which are suggestive of copying processes at work in reproduction (Bowler 2001, pp. 85–86). Embryologists’ attention gradually turned away from speculative edifices such as recapitulation theory, and instead towards experimentation and the search for physiological mechanisms (Bowler 2001, p. 77).
It was in this context that August Weismann (1891, p. 190) became a key supporter of hard heredity, in a research program aimed at synthesizing Darwinian theory and the cytology of his day. After initially accepting the inheritance of acquired characteristics (Weismann 1882), Weismann rejected it on the basis of both theoretical and philosophical arguments (the theory of natural selection is sufficient to explain adaptation), as well as cytological arguments (no mechanism for the transmission of acquired traits is known; moreover, it seems impossible to translate a trait into a hereditary determinant) (Weismann 1893b, Chapter XIII, 1893a, pp. 107–108, 1904, p. 63). Weismann assumes that in multicellular organisms, only the germ line is immortal and involved in the transmission of traits, and that the somatic line cannot alter it in a directed way (Bowler 2001, p. 88). Traits are assumed to be predetermined by chromosomes, and differentiation occurs through an asymmetrical distribution of chromosomes between daughter cells (ibid., p. 75). This position was notoriously characterized as nuclear preformationism, reactivating a cleavage with the proponents of epigenesis (Hertwig 1894; Wilson 1896, pp. 327–331) – it should be remembered, however, that in preformation, the form pre-exists and only grows; in Weismann, it is the potential of a form that pre-exists (Bowler 2001, pp. 75–76, 81). Defending his position with a vigor that tended towards dogmatism, Weismann exacerbated tensions with advocates of soft heredity, who called him a “neo-Darwinian”, so as to distinguish his position from that of Darwin himself (Romanes 1888; Bowler 2001, p. 89). The late Weismann was greatly influenced by his contemporary Hugo De Vries (Bowler 2001, p. 90). From Darwin’s pangenesis, De Vries retains the idea of particles (which he calls “pangenes”) responsible for traits; but for him, these remain in the cell (they are supposed to group around chromosomes and leave the nucleus for trait expression). All cells possess them in their entirety, even in latent form, and their number is perhaps limited, as traits develop through their interactions: heredity can thus take place without mixing, and new traits, even new species, appear through mutation (Vries 1889, sec. iv; Bowler 2001, pp. 90–91).
The year 1900 saw the rediscovery of Mendel’s laws – or rather, the reinterpretation of Mendel’s work in light of the gradually emerging framework of Mendelian genetics (Correns 1900; Tschermak 1900; Vries 1900; see Bowler 2001, pp. 113–116). Embryologists such as Thomas Morgan, frustrated by the failure of their experimental techniques to explain trait formation, turned to hybridization experiments that only studied transmission (Bowler 2001, p. 78, 82). These early Mendelians produced a vision of transmissible variation that was discrete, underpinning a saltatory, non-selective vision of evolution in direct opposition to that of the neo-Darwinians (notably the so-called biometricians), for whom evolution is gradual and based on the natural selection of continuous variation, fiercely opposing Mendelism (Gayon 1992, Chapter VII–VIII). This was also the time when, in tandem with developments in cytology, the chromosomal theory of heredity developed, with Mendelian overtones: chromosomes would be the medium for determining traits (Sutton 1903; Boveri 1904). Many people resisted this theory, including leading geneticists such as Morgan (who was converted to it, in a particularly fruitful Drosophila genetic mapping program), as well as William Bateson and Wilhelm Johannsen, for whom the hereditary determinants of traits needed to be conceived holistically, in terms of energy levels or waves in the cell (Bateson and Mendel 1902, pp. 2–3; Morgan 1910, 1913; Morgan et al. 1915; Johannsen 1923; see Coleman 1970; Allen 1974; Darden 1977; Roll-Hansen 1978; Allen 1978, cited by Morange 2020, Chapter 26; Bowler 2001, pp. 120–121, 129–131; Roll-Hansen 2014). It was, however, Bateson who founded the first Mendelian school of genetics in Great Britain, and Johannsen, who is credited with establishing the concepts of gene (a contraction of the pangene, the determinant of hereditary traits), genotype (the set of genes) and phenotype (a measurable trait) (Johannsen 1909, p. 113, 1911, pp. 132–134). These conceptual distinctions were part of a conquering movement to base the study of heredity and evolution on experimentation, and to exclude approaches that were deemed to be more descriptive or speculative, such as morphological or biometric studies (Sapp 1987, pp. 21–22, 36–41). In so doing, Johannsen was careful not to forge hypotheses concerning the physical support of hereditary material: for him, genetics did not study genotypes, but genotypic differences (Johannsen 1911, p. 133; see Wanscher 1975; Roll-Hansen 2014). Even though the chromosomal and Mendelian theory of heredity was fairly generally accepted in the community around 1915, particularly across the Atlantic (Morgan et al. 1915; Sapp 1987, pp. xiii, 46–48, 221), where it founded what would later be called classical genetics (Bowler 2001, p. 128), the Mendelian gene remained a mainly abstract entity – not a speculation, but a computational tool used to describe the results of hybridization experiments (East 1912, p. 634; Morgan 1935, p. 315; see Stent 1970, p. 910; Bowler 2001, p. 125; Rheinberger et al. 2015). Thus, crystallized, classical genetics put aside the question of trait formation to focus solely on their transmission (Sapp 1987, Chapter 2; Bowler 2001, p. 129).
The American school of genetics founded by Morgan rapidly gained in power: it was an opportunity to secure posts and funding, with the promise of applications in both agriculture and public health, with the eugenics program (Sapp 1987, pp. 46–47; Bowler 2001, pp. 132–137). In evolutionary biology, the development of population genetics reconciled Mendelism with neo-Darwinism: continuous transmissible variation – which was dear to biometricians – could be supported by the interaction of multiple Mendelian genes, each causing small differences (Fisher 1918; Fisher 1930; Wright 1931; Haldane 1932; see also Yule 1902). However, classical genetics did not totally reign supreme. The chromosomal theory hardly shuts down the paradox, in multicellular organisms, of cellular differentiation taking place under the control of genes that are assumed to be identical, and active, in all cells (Sapp 1987, p. 17). Cases of non-Mendelian heredity have been reported, particularly in plants (Baur 1908; Correns 1909a, 1909b; Sapp 1987, p. 26, 73–74). Ultimately, as they themselves admit, geneticists have failed in their attempts to produce new species in the laboratory (Sapp 1987, p. 17, 21–22).
The Germans and the French, in particular, resisted the objects of study of classical genetics: for them, the topic of interest related to trait formation; Mendelians studied the transmission of trivial traits, with no biological relevance (Sapp 1987, Chapter 3, Chapter 5; Bowler 2001, pp. 143–152). Embryologists notably saw the cytoplasm of the egg cell as the essential element determining the properties of the organism, and encouraged research into cytoplasmic heredity in open opposition to the nuclear, then chromosomal, theory of heredity (contra Morgan et al. 1915; Morgan 1926; see Sapp 1987, p. xiii, 3, 27, 56). Research on cellular organelles experienced renewed interest (Sapp 1987, p. 25); the cell appears, beyond the resolution of the microscope, as an ordered system of particles (whose size can be supramolecular, and called “colloids”) where chemical reactions of incalculable diversity take place (Wilson 1923; Sapp 1987, p. 18, 213–214), and which can form a “field” of metabolic gradients (Sapp 1987, p. 144); the cytoplasm is supposed to harbor “plasmagenes” (plasmatischen Gene), self-replicating microscopic elements that are differentially distributed between daughter cells (Winkler 1924), or to constitute a reactive, integrated, transmissible system that conditions trait expression, known as the “plasmon” (Wettstein 1926), which is the plasma complement of the “genome” (Winkler 1920, p. 165), in other words, the set of chromosomes (Sapp 1987, pp. 72–86, 2003, pp. 174–175).
In Europe, many geneticists are actively involved in cytoplasmic heredity research (Sapp 1987, p. 14, 54–55, 69, 73, Chapter 4, Chapter 5). Across the Atlantic, the differences between schools are more powerful: when a biologist of Jewish descent such as Victor Jollos, known for his discovery of Dauermodifikationen (environmentally induced variations transmissible over hundreds of vegetative generations in paramecia (Jollos 1920, 1921; Hämmerling 1929)) fled Germany for the US in 1934, he found it impossible to valorize his work and find a job again (Sapp 1987, pp. 62–65; Bowler 2001, pp. 148–149).
1.4. Classical epigenetics
It is in this context of resistance to classical genetics (as well as to the neo-Darwinism of this period, which reduces evolution, in its most extreme form, to dynamics of gene frequencies (e.g. Dobzhansky 1937, p. 11)) that Conrad Waddington coined a word to designate this study that was put aside by early geneticists: recalling the notion of epigenesis – perhaps, it must be said, rather vaguely (see Koltzoff 1935; Waddington 1956a; Wightman 1956) – he called the study of developmental processes that link genotype and phenotype “epigenetics” (Waddington 1942); see also Waddington 1939, pp. 154–156; Waddington 1957, p. ix, 151; cited by Haig 2004; Nicoglou and Merlin 2017). He calls this complex of developmental processes epigenotype. The reference to process is not random: Waddington is a reader of Alfred North Whitehead, the English mathematician and philosopher who built a philosophy of process (Whitehead 1925, 1929; Boisseau 2023). Waddington also suggests visualizing the development of an organism through a metaphor: that of a ball rolling down a landscape of hills and valleys. The genotype determines the landscape, which Waddington would later call the epigenetic landscape, in other words, the developmental potentials that are or are not actualized in the phenotype during development by the organism’s interaction with its environment (Waddington 1939, 1940, 1957). Here again, these categories of potential and actual are the tacit and classic Western heritage of Aristotelian categories (ca. 350 BCE), see (Aristotle 1879, 1986; Cohen and Reeve 2021). Waddington created these concepts at a time when the notion of a gene remained abstract: it was a difference causing differences, the material support for this causality not being clearly identified at the time. As a result, Waddington’s concepts bear the mark of this abstraction, making them highly flexible in terms of their material interpretation.
While the notion of the epigenetic landscape met with some success, particularly in the field of morphogenesis (Berry and Searle 1963; Herring 1993; cited by Haig 2004), Waddington’s concepts of epigenetics and epigenotype did not catch on: apart from Waddington himself, hardly anyone referred to them, and these words were later independently reinvented to name different concepts. Waddington’s real success was posthumous: from the 1990s and especially 2010, a new generation of evolutionary thinkers sought to extend evolutionary theory to reduce the explanatory share allocated to gene dynamics alone (Jablonka and Lamb 2002; Slack 2002; West-Eberhard 2003; Jablonka and Lamb 2005, pp. 63–64; Pigliucci and Müller 2010; see Morange 2009; Gilbert 2012; Haig 2012; Jablonka and Lamm 2012; Morange 2020, pp. 328–329). This new generation is re-appropriating Waddington’s concepts (in what may look like a quest for historical legitimacy), and references to his work are multiplying.
1.5. Molecular epigenetics
Around the 1940s, biology became molecular, with the development of new techniques (crystallography, electrophoresis, etc.) and new models (fungi, bacteria, viruses, algae, protozoa) (Sapp 1987, pp. 88–89; Bowler 2001, p. 175; Rheinberger et al. 2015). Geneticists began to focus on the gene control of physiology and turned to microorganisms, which freed them from the complexities of cellular differentiation (Sapp 1987, p. 88). It was at this point that work on the Neurospora fungus suggested that each step of a metabolic pathway is under the control of a single gene (Beadle and Tatum 1941; Sapp 1987, p. 133), a result often summarized (somewhat anachronistically) as the “one gene – one enzyme” hypothesis (Morange 2020, Chapter 2). Work on bacterial transformation and bacteriophages suggests that the material support for genes is DNA (Avery et al. 1944; Hershey and Chase 1952; see Bowler 2001, p. 175; Morange 2020, Chapter 4). This vision is not self-evident: for many, DNA is not complex enough to carry genes; proteins are better candidates; on the other hand, the generality of results obtained on viruses and bacteria is questionable (Bowler 2001, pp. 174–175; Morange 2020, pp. 19–20, 35–39). However, when James Watson and Francis Crick proposed that the structure of DNA is a double helix, on the basis of X-ray diffraction patterns obtained by Rosalind Franklin and Raymond Wilkins, their model made it possible to explain both how genetic information can be encoded in DNA (via base sequence) and how this information can be replicated (via base complementarity) (Franklin and Gosling 1953; Watson and Crick 1953; Wilkins et al. 1953; see Bowler 2001, p. 176; Morange 2020, Chapter 11). The notion of a genetic code matching DNA and protein sequences quickly took root, and biologists tried to approach it from both the information-theoretic side (as a code to be broken) and the biochemical side – the latter ultimately being successful (Sarkar 1996)2.
The domestication of microorganisms and the development of hybridization methods were accompanied by a broadening notion of heredity: the heredity of microorganisms became a model of the cellular heredity expressed during differentiation in multicellular organisms (viruses were also seen as vectors of heredity) (Sapp 1987, p. 89). However, this domestication of microorganisms ushered the discovery of many apparently non-Mendelian phenomena: for proponents of cytoplasmic heredity, genetics was on the eve of a major revolution that could mark the end of Mendelian supremacy and place the cytoplasm at the center of cellular functioning (Ephrussi 1953; see Waddington 1953; Sapp 1987, pp. 89, 166), thereby renewing the question of the evolutionary importance of the cytoplasm (Waddington 1940, p. 53; quoted by Sapp 1987, p. 101). A series of works are interpreted as marking the independence (if not pre-eminence) of non-nuclear cellular phenomena from the nucleus, involving, for example, the cell cortex or basal bodies (Just 1932, 1939; Lwoff 1990). In addition to this scientific turmoil, there was a political aspect: in the context of the Cold War, supporters of Lysenkoism (a scientific ideology that was then dominant in the USSR, defending a holistic vision of soft heredity) seized on work on cytoplasmic heredity to discredit Morgan’s work on chromosomal Mendelism, generating a controversy discussed daily in Western newspapers and directly interfering with the development of research programs (Sapp 1987, Chapter 6, p. 172, 183). Various models of cytoplasmic heredity were proposed, involving plasmagenes (Lwoff 1949; Sonneborn and Beale 1949; Lwoff 1950; Morange 2020, p. 145) or metabolic feedback loops generating environmentally inducible and stable states (Wright 1945; Delbrück 1949; see Novick and Weiner 1957; Jablonka and Lamb 1995, pp. 82–83; Morange 2020, p. 327). Subsequent research was established around the transmission of supramolecular cellular structures, such as cortical structures in paramecia (Beisson and Sonneborn 1965; Nanney 1968), and cytoplasmic genes, now understood as nucleic acids (Sager 1972).
At the height of research into cytoplasmic heredity, the cytoplasm was presented, in opposition to the nucleus, as a highly responsive interface that could explain cellular differentiation. However, this “geographical” opposition was soon to be dissolved by the conceptual changes introduced by molecular biology (Sapp 1987, pp. 192–200). By the end of the 1950s, it had become clear that genes could be regulated: nuclear phenomena could therefore explain differentiation (ibid., p. 193). This molecularization of genetics gave rise to the a concept of epigenetics, proposed by Nanney (1958a).
Initially, a supporter of cytoplasmic heredity, Nanney took on the vision of cytoplasmic heredity as the only possible explanation of cellular differentiation (Sapp 1987, p. 199). For Nanney, the whole question of heredity, posed in “geographical” terms (nucleus/cytoplasm, soma/germen), is badly put forward, both conceptually and empirically (Nanney 1957, p. 143; quoted by Sapp 1987, p. 200). A “totalitarian” vision of genetic mechanisms, in which genes are the only relevant determinants of traits, must be instead contrasted with a more interactive (“democratic”) vision, in which biological organization is perpetuated as a stationary state by the interaction of its constituents (Nanney 1957; quoted by Haig 2004). At a conference on extrachromosomal heredity organized by Boris Ephrussi at the Centre de Génétique Moléculaire that he founded in Gif-sur-Yvette (Sapp 1987, Chapter 5), Nanney proposed that, in addition to a “library of specificities” produced by “genetic control systems”, there are “auxiliary mechanisms”, determining which “specificities” will be expressed in each cell, which he calls “epigenetic systems” (Nanney 1958a, p. 712). Although he refers to Waddington (1956b) after the fact, it seems that Nanney coined the term epigenetics independently, having first thought of calling these mechanisms “paragenetic” (Ephrussi 1958, p. 46; Haig 2004). Inflecting his concept, Nanney then proposed to see epigenetic systems as signal interpretation systems (that is, interpreting genetic signals), whose causal ability is constrained by the information contained in the genetic library, and which, he admitted, probably do not lead to irreversible changes (Nanney 1958b; quoted by Haig 2004). The terminology was defended by Ephrussi (1958, p. 47), who, from the perspective of a taxonomy of cytoplasmic heredity, took Nanney’s criticism of a “geographical” taxonomy to heart. Ephrussi thus distinguishes genetic mechanisms (based on the “transmission of particles carrying their own structural information”) from epigenetic mechanisms (“involving functional states of the nucleus”). In a commentary, Joshua Lederberg (1958, p. 384) embraces the concept, but not the term, which, he notes, is already used in a very different sense by Waddington (1952). Lederberg (1958, p. 385) prefers to distinguish between nucleic information (dependent on the sequence of nucleotides in a nucleic acid), epinucleic information (dependent on other aspects of the nucleic acid such as the presence of polyamines or polypeptides) and extranucleic information (dependent on molecules and reaction cycles that are not directly connected to the nucleic acid). Ironically, our current concepts are closer to Lederberg, and our terminology is from Nanney (Haig 2004).
The dichotomy between genetics and epigenetics has taken root: by the mid-1960s, it seemed sufficiently well known that it no longer required a definition in the literature (Cahn and Cahn 1966; Markert 1968; cited by Haig 2004). It has applications in a variety of fields, such as the biology of cancer (proposed as the result of an epigenetic mutation) or research into isozymes, enzymes with different sequences that catalyze the same reactions (Haig 2004). The term epigenotype was reinvented, this time to designate the set of self-replicating regulatory mechanisms that characterize the various cell lineages – under Waddington’s approving view, who noted that he had already coined the term, with a different meaning (Abercrombie 1967; cited by Haig 2012). However, the early successes of epigenetic terminology were modest and, with the exception of isozymes, the association of what we would now call epigenetic research with the term itself remains anecdotal (see Morange 2002).
1.6. Epigenetics without knowing it, or Mr. Jourdain’s epigenetics
Biology is first and foremost involved in epigenetics without knowing it, “à la Monsieur Jourdain”3, in a disciplinary permeability context that is reminiscent of the intricacy of the mechanisms studied.
Barbara McClintock can be considered one of the first molecular epigeneticists before the word. Known today for her discovery of transposons, she conceived of them as elements controlling gene expression, in a highly organicist vision of biological functioning (McClintock 1948, 1951). However, two decades elapsed between her first publications and the genetic community’s acceptance of her results – her results, but not so much her vision, organicism being cast aside (Keller 1983, Chapter 8, p. 193). Another heavyweight of genomic organicism, Richard Goldschmidt (1916, 1954), was similarly marginalized (Allen 1974; Keller 1983, p. 70, 98). While transposition can be seen today as a genetic phenomenon, this has not always been the case: Michel Morange (2002) notes that the dedicatee of the book Epigenetic mechanisms of gene regulation is McClintock herself (Russo et al. 1996). In a reverse move, Gary Felsenfeld (2014) counts the work of geneticist Hans Muller (1930) on chromosomal rearrangements caused by X-ray irradiation as precursors of epigenetics (see Carlson 1971).
In France – where, as we have said, a certain tradition exists that focuses on trait formation rather than transmission – Elie Wollman and François Jacob proposed a model similar to McClintock’s, based on their work on bacterial conjugation, in which cellular differentiation (and, in a later version, regulation alone) would be under the control of genome modifications caused by mobile elements, “episomes” (Jacob and Wollman 1959, 1961; see Morange 2002). Work by Jacques Monod and other colleagues suggests other models of non-genetic differentiation, this time through the induction of enzyme formation by substrate molecules (such as the induction of lactose permease by intracellular lactose in Escherichia coli), with different stable states that can be achieved in the same environment (Monod 1956; Cohen and Monod 1957; see Thieffry 1996; cited by Morange 2002). Such models culminate in Jacob and Monod’s operon model, in which a repressor (an allosteric protein encoded by a regulatory gene) binds to an inducer, with the conformational change of the allosteric repressor (and thus its binding capacity) depending on the presence of regulatory ligands (Jacob et al. 1960; Jacob and Monod 1961; see Morange 2002, 2020, p. 154). The allosteric model also provided the basis for the first model to explain the possible infectivity of a protein, the prion (Griffith 1967; Morange 2002).
The operon model is a geneticist’s answer to the question of how traits are formed (and no longer simply transmitted); it provides the opportunity to forge a powerful metaphor, that of the genetic program: gene regulation would be comparable to the execution of a series of instructions (Jacob and Monod 1961, p. 354; Morange 2002, p. 55). This metaphor became fashionable in the late 1960s, and Jacob (1970) developed it further in La Logique du vivant: unlike a computer program, the genetic program requires its own outputs to be executed. For Jacob, the genetic program resolves the old unease between epigenesis and preformation: the egg does not contain the description of the future organism, but the instructions enabling it to develop in time and space (Jacob 1978, p. 249; quoted by Morange 2002, p. 55). The genetic program metaphor would go on to be severely criticized on philosophical and theoretical grounds, with its apparent determinism hardly relating to the improvisational capacity of biological systems (Morange 2002; Longo and Tendéro 2008; Pocheville 2018), but it only really fell out of favor from the 2000s onwards, in the post-genomic era – a time when the epigenetic reprogramming metaphor was gaining ground (Holliday 1990; Reik et al. 1993, 2001; Morgan et al. 2005; Suvà et al. 2013; see Brandt 2010).
The operon model is based on three assumptions: genetic material is stable during cell functioning (an assumption dating back to De Vries and Morgan); gene expression is controlled at the transcriptional level; and, lastly, this control is achieved by the binding of specific regulatory proteins to DNA (Morange 1997). While this vision of regulation has been successful to the point of turning to “mania” (ibid., p. 384), it has also led to reactions: for a whole section of the community, the operon cannot constitute a general explanation of regulation and differentiation, particularly in eukaryotes, where there is a lack of proof of its existence (Morange 1997, 2002, 2013). A series of alternatives have been proposed, such as the control of gene expression at the translation level (thanks to the stability of certain RNAs), at the DNA sequence level through gene amplification or reverse transcription, or at the enzymatic activity level (Morange 1997). Among these alternatives, those concerned with the regulation of transcription via structural and chemical modifications of DNA, histones and cytosine methylations, will be of particular interest to us.
The history of research into histones and DNA methylations is “long and tortuous”, with the two fields developing in a remarkable lack of communication (Morange 2013, p. 453). The hypothesis that histones can inhibit gene activity was first speculatively proposed in the early 1950s (Stedman and Stedman 1950; Morange 2013, p. 451, 2020, p. 329). Histone modifications (acetylation and methylation) were described 10 years later, with the first in vitro results confirming histone inhibitory activity (Huang and Bonner 1962; Allfrey et al. 1963), as well as the role of acetylation in lifting this inhibition: the histone can function as a specific switch of gene activity (Allfrey and Mirsky 1964; Allfrey et al. 1964; Georgiev 1969; see Paik et al. 2007, p. 148; Morange 2013, p. 451, 2020, p. 329; Felsenfeld 2014, p. 5). However, these initial results were received with skepticism (Morange 2013, p. 451). Eric Davidson, for example, considered that in eukaryotes, inhibition of gene activity could not be achieved by specific repressors, the encoding of which would require too many genes; he preferred a model of gene regulation in which histones play a structural and global inhibitory role (the default state of the genome being inactivity), with activation by specific activators that he proposed to identify with RNAs (Davidson 1968, pp. 313–325; Morange 2013, p. 452). This model, subsequently developed with Roy Britten, has the advantage of predicting switches between global patterns of gene expression, which seem more plausible than cascades of local regulation to explain differentiation (Britten and Davidson 1969, p. 351; Morange 2002, p. 55, 2020, p. 268; García and Suárez 2010). Histones then appear to have a non-specific inhibitory activity; moreover, Morange (2013, p. 452) notes that the discovery of the nucleosome (Kornberg 1974; Olins and Olins 1974) and its subsequent characterization (Richmond et al. 1984) focused attention on the role of histones in chromatin structure (Kornberg 1977; McGhee and Felsenfeld 1980), with the suggested effect of their modifications on transcription remaining unknown (Holt 1985; Grunstein 1990) – at least until the 1990s, when proteins that recognize these modifications and act on transcription began to be discovered (Turner 1991; Wolffe 1994; Pazin and Kadonaga 1997; Kuo and Allis 1998; Kouzarides 1999; see also Felsenfeld 2014, p. 5; Morange 2020, p. 330).
As for cytosine methylations (5mC: 5-methylcytosine) of nucleic acids, results indicating their existence marked the first half of the 20th century (Wheeler 1904; Johnson and Coghill 1925; Hotchkiss 1948; see Mattei et al. 2022). The 1950s saw confirmation of their presence in variable quantities in plant and animal DNA (Wyatt 1950, 1951; Mattei et al. 2022), and as early as the 1960s, their potential role in eukaryotes was discussed: 5mCs could protect DNA (Srinivasan and Borek 1964) or, on the contrary, induce specific mutations that would participate in the differentiation process (Scarano et al. 1967) – this was a hypothesis, however, that was incompatible with recent results from cloning experiments (Gurdon 1962; see Morange 2013, p. 452). However, it is in prokaryotes that the first results flourished, thanks in particular to the in-depth description of the restriction-modification system (R-M system) in bacteria, a system in which so-called “restriction” enzymes cut DNA at specific sites via recognition of particular sequences (generally four to eight nucleotides long) (Luria and Human 1952; Luria 1953; Lederberg 1957; Gold et al. 1963; Arber 1965; Arber and Linn 1969; Morange 2013, p. 452, 2020, p. 331; Mattei et al. 2022). A bacterium possessing this system can digest the DNA of an infecting virus, the bacterial DNA being protected at the restriction sites by species-specific methylations (Arber 1965; Mattei et al. 2022). In addition to the role this system played in early genetic engineering experiments in the early 1970s (Jackson et al. 1972) and in the study of methylations themselves (Bird 1978; Bird and Southern 1978), it offers a possible analogy with the putative role of methylases in eukaryotic development (Morange 2013, p. 452, 2020, pp. 181, 331): the latter could recognize specific sites and control gene expression during differentiation, a mechanism that could explain the recently discovered inactivation of the X chromosome in mammals (a hypothesis that was later ruled out) (Lyon 1968; Lock et al. 1987; Morange 2013; Mattei et al. 2022, p. 12), as well as DNA loss during development in certain eukaryotes or senescence and apoptosis (Adams 1973; Holliday and Pugh 1975; Riggs 1975; Sager and Kitchin 1975; see Morange 2013, 2020, pp. 331–332; Mattei et al. 2022). That being said, this hypothetical ability of methylases to recognize specific sites has not been confirmed by subsequent studies (Morange 2013). While the precise role of methylations in the regulation of gene expression remains unknown (Felsenfeld and McGhee 1982; Doerfler 1983; cited by Morange 2013), converging studies based on improved locus-specific 5mC detection methods suggest that 5mCs are antagonistic to expression (Southern 1975; Waalwijk and Flavell 1978; Kuo et al. 1979; Mandel and Chambon 1979; McGhee and Ginder 1979; see Mattei et al. 2022). During the 1980s, technical advances (such as the possibility of inserting methylated or unmethylated DNA fragments into living cells) led to a more precise role for 5mC and, at least for mammals, a consensus emerged that 5’ promoter methylation inhibits transcription (Mattei et al. 2022). However, the absence of 5mC in model organisms such as the yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans and the vinegar fly Drosophila melanogaster, leaves the community dubious as to the generality of the mechanism (Morange 2013, 2020, p. 333; Mattei et al. 2022). It was at this point that Robin Holliday (1987), in a well-received speculative article, revived the question of the heritability of cellular states via methylations, and their possible role in evolution, formulating it in an explicitly epigenetic framework (for which he credited Waddington) that would briefly catalyze the association in molecular biology between “epigenetics” and heritable methylations (Holliday 1994; Haig 2004; Morange 2020
