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Since the discovery of DNA as the support of genetic information, the challenge for generations of life scientists was to understand the mechanisms underlying the process that translate the sequence of a gene to a phenotype. In the 1950s, the concept of epigenetics was defined by the British biologist Conrad H. Waddington as the study of "epigenesis" that governs the biological processes involved in the development of any organism. The term epigenetics, now best defined as "above the DNA sequence" reflects the gene-environment interactions by which genes determine traits. Since, its first description, studies underlying the mechanisms involved in these processes has led to an increasing understanding of the regulation all genome transactions such as transcription, replication, repair and the biological pathways coordinated by these mechanisms. We will discuss here the main principles regulating epigenetic processes, their roles in physiology, their evolution over the life time and their implications in medicine., (Copyright © 2023 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Adult skeletal muscle is composed of thousands of fibers (also called myofibers) that contract thus allowing voluntary movements. Following an injury, muscle stem cells, surrounding the myofibers, activate, proliferate, and differentiate to form de novo myofibers. These steps constitute a process called adult (or regenerative) myogenesis. This process is possible thanks to various transcription factors sequentially expressed and regulated by epigenetic factors that modulate the chromatin and therefore lead to the regulation of gene expression. Gene expression changes consequently affect the fate of muscle stem cells. Histone Lysine Methyltransferases methylate some histones involved in the repression of gene expression. We describe here the role of SETDB1 during adult myogenesis, notably its role during muscle stem cell differentiation., (© 2023 médecine/sciences – Inserm.)

Giant cell tumors of bone (GCTs) are rare mesenchymal tumors classified as intermediate in the WHO 2020 classification, i.e. neither completely benign nor definitely malignant, due to recurrence (frequent) and pulmonary metastases (rare). They involve the end of long bones as well as the axial bones of mature skeletons. They are made of mononuclear stromal tumor cells of (pre-) osteoblastic phenotype, mononuclear cells of the monocyte-macrophage lineage and osteoclast-like multinuclear giant cells responsible for tumor osteolysis. In 95% of cases, the stromal cells have a specific mutation in the H3F3A gene which encodes histone H3.3. The mutated H3.3 G34W protein (90% of cases) can be easily detected by immunohistochemistry, even on small samples. Many tumors or bone pseudotumors contain osteoclast-like giant cells, cells of the bone microenvironment, and should not be confused with GCT: mainly brown tumor of hyperparathyroidism, aneurysmal bone cyst, chondroblastoma, non-ossifying fibroma and central giant cell granuloma., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: The etiology of autism spectrum disorders (ASD) is complex and multifactorial, and the roles of genetic and environmental factors in its emergence have been well documented. Current research tends to indicate that these two factors act in a synergistic manner. The processes underlying this interaction are still poorly known, but epigenetic modifications could be the mediator in the gene/environment interface. The epigenetic mechanisms have been implicated in susceptibility to stress and also in the pathogenesis of psychiatric disorders including depression and schizophrenia. Currently, several studies focus on the consideration of the etiological role of epigenetic regulation in ASD., Object: The object of this review is to present a summary of current knowledge of an epigenetic hypothesis in ASD, outlining the recent findings in this field., Methods: Using Pubmed, we did a systematic review of the literature researching words such as: autism spectrum disorders, epigenetics, DNA methylation and histone modification., Results: Epigenetic refers to the molecular process modulating gene expression without changes in the DNA sequence. The most studied epigenetic mechanisms are those that alter the chromatin structure including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. In ASD several arguments support the epigenetic hypothesis. In fact, there is a frequent association between ASD and genetic diseases whose epigenetic etiologies are recognized. A disturbance in the expression of genes involved in the epigenetic regulation has also been described in this disorder. Some studies have demonstrated changes in the DNA methylation of several autism candidate genes including the gene encoding the oxytocin receptor (OXTR), the RELN and the SHANK3 genes. Beyond the analysis of candidate genes, recent epigenome-wide association studies have investigated the methylation level of several other genes and showed hypomethylation of the whole DNA in brain and blood samples of autistic patients. The changes in epigenetic marks following exposure to environmental factors known as autism risk factors are also discussed in many reports. They include nutritional (vitamin D and folate) and toxic (sodium valproate, bisphenol A) factors. Despite a considerable contribution to understanding the complexity of ASD etiology, the epigenetic studies suffer from numerous methodological biases that limit the scope of their results and make their interpretation difficult. The cell samples used in the psychiatric studies are mostly from the post-mortem tissue of the central nervous system, and factors that might change the epigenome (age, gender, treatments received…) are not taken into account. The use of blood and buccal epithelium samples raises in turn the question as to whether the epigenome of these cells reflects that of the nerve cells. DNA methylation can also be influenced by cell subcomposition variability, transcriptional variability and by DNA sequence variants., Conclusion: These recent discoveries in epigenetics are the beginnings of an etiopathogenic research revolution in neurodevelopmental disorders. The conceptualization of epigenetic processes is in its early stages and despite its limited means will help integrate disparate data factors previously involved in autism. It could also be the target for the development of new therapeutic modalities., (Copyright © 2016 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Schizophrenia and other psychoses are categorical psychiatric diagnoses corresponding to frequent and heterogeneous disorders. Their physiopathology still remains largely unknown despite numerous recent advances. In particular, the last decade has identified different types of genetic variants, thanks to emergence of high-throughput methods. These methods allow both the identification of rare variants with a large effect such as punctual mutations or copy-number variants and the identification of frequent variants with a limited effect such as polymorphisms. Many impacted genes have been identified showing a very high genetic heterogeneity of psychoses. These genes are overrepresented in synaptic and neurotransmission pathways. Only a small fraction of psychoses could be easily explained by genetics but this screening in clinical practice is important as it can lead to therapeutic challenge or genetic counselling. Nowadays, it is clear that the pathophysiology of the psychoses can only be understood by an integrative approach taking into account the interaction between genes and environment. This interaction could be mediated by the epigenome defined as the modification of gene expression without changes in DNA sequence. Epigenome is stable but could be modified by environmental factors. Several epigenetic mechanisms have been studied in psychosis, in particular the DNA methylation, the modification of histones and the microRNA. All of these mechanisms are under regulation by genetic factors and variants in these epigenetic-involved genes and cofactors have been also associated with schizophrenia. Thus, pathophysiology of psychosis is complex and morestudiesare needed before definitive conclusions. Altogether, the recent advances in the genetics and epigenetics of psychosis are promising and could open the way to a recategorization of these disorders as well as the identification of new therapeutic targets., (© Société de Biologie, 2017.)

In the nucleus of eukaryotic cells, the chromatin states dictated by the different combinations of histone post-translational modifications, such as the methylation of lysine residues, are an integral part of the multitude of epigenomes involved in the fine tuning of all genome functions, and in particular transcription. Over the last decade, an increasing number of factors have been identified as regulators involved in the establishment, reading or erasure of histone methylations. Their characterization in model organisms such as Arabidopsis has thus unraveled their fundamental roles in the control and regulation of essential developmental processes such as the floral transition, cell differentiation, gametogenesis, and/or the response/adaptation of plants to environmental stresses. In this review, we will focus on the methylation of histones functioning as a mark of activate transcription and we will try to highlight, based on recent findings, the more or less direct links between this mark and gene expression. Thus, we will discuss the different mechanisms allowing the dynamics and the integration of the chromatin states resulting from the different histone methylations in connection with the transcriptional machinery of the RNA polymerase II., (© Société de Biologie, 2017.)

Chronic drug exposure alters gene expression in the brain, which is believed to underlie compulsive drug seeking and drug taking behavior. Recent evidence shows that drug-induced long-term neuroadaptations in the brain are mediated in part by epigenetic mechanisms. By remodeling chromatin, this type of regulation contributes to drug-induced synaptic plasticity that translates into behavioral modifications. How drug-induced alterations in DNA methylation regulate gene expression is reviewed here, with a focus on MeCP2, a protein binding methylated DNA. The importance of histone modifications, especially acetylation is also discussed, with an emphasis on the effects of inhibitors of histone deacetylases on drug-induced behavioral changes. The precise identification of the epigenetic mechanisms that are under the control of drugs of abuse may help to uncover novel targets for the treatment of drug seeking and relapse., (© 2015 médecine/sciences – Inserm.)

The environment, defined broadly by all that is external to the individual, conditions the phenotype during development, particularly the susceptibility to develop non-communicable diseases. This notion, called Developmental Origins of Health and Disease (DOHaD), is based on numerous epidemiological studies as well as animal models. Thus, parental nutrition and obesity can predispose the offspring to develop metabolic and cardiovascular diseases in adulthood. The known underlying mechanisms include an altered development of tissues that adapt to maternal metabolic condition, and a placental dysfunction, which in turn impacts fetal growth and development. Epigenetic mechanisms modulate gene expression without affecting the DNA sequence itself. The main epigenetic marks are DNA methylation and histone post-translational modifications. These marks are erased and set-up during gametogenesis and development in order to ensure cellular identity. Therefore, they can lead to a memorisation of early environment and induce long-term alteration of cell and tissue functions, which will condition the susceptibility to non-communicable diseases. The placenta is a programming agent of adult disease. The environment, such as smoking or psychosocial stress, is able to modify epigenetic processes in placenta, such as small RNA expression and DNA methylation. We showed that placenta is sensitive to maternal obesity and maternal nutrition, in terms of histology, transcription and epigenetic marks. A clear sexual dimorphism is remarkable in the placental response to maternal environment. In adulthood, the phenotype is also different between males and females. Epigenetic mechanisms could underlie this differential response of males and females to the same environment. The DOHaD can no longer be ignored in Biology of Reproduction. The prevention of non-communicable diseases must take this new paradigm into account. Research will allow a better comprehension of the mechanisms of this early conditioning and the marked sexual dimorphism it is associated to., (© Société de Biologie, 2015.)

The second half of the 20th century has been dominated by genetic models of tumors that provided conceptual tools explaining tumor genesis and its evolution. Other domains--epigenetics, cell metabolism--appeared that generated a more complex landscape of tumor physiopathology. Moreover, the discovery of tumor stem cells and intratumoral heterogeneity are likely to explain recurrence. A major difficulty is that every tumor behaves as an organ that evolves in function of its microenvironment. By integrating all the new data in more and more sophisticated models, the major goals may emerge from the characterisation of new markers for diagnosis and prognosis and from the selection of pertinent and efficient new therapeutic targets.

In mammals, the post-meiotic phases of spermatogenesis direct a drastic compaction of the genome characterized by the replacement of the majority of histones by small basic non-histone proteins, transition proteins followed by protamines. Although the mechanisms controlling this process are poorly understood, available data suggest that the nucleosome, which represents the universal unit of genome organization in eukaryotes, is the target of specific events cooperating to globally transform DNA organization at a genomic scale. Indeed, after meiosis, nearly all nucleosomes associated with the male genome undergo successive modifications increasing their instability, finally leading to their dissociation and re-organization. The characterization of the underlying mechanisms is a real challenge and appears as essential for the understanding of male gametogenesis and associated pathologies., (© 2012 médecine/sciences – Inserm / SRMS.)

Vitamin B6 is well-known for its role as a cofactor in many enzymatic reactions and recently, several epidemiological studies have highlighted the importance of this vitamin as a protective agent against various cancers: elevated vitamin B6 plasma levels were associated with a lower risk of colorectal cancer development, for example. In vivo studies have shown that vitamin B6 decreased cell proliferation and enhanced the immune response. At the cellular level, antioxidant, pro-apoptotic and anti-angiogenic effects have been identified. At the molecular level, vitamin B6 is able to inhibit the transactivation potential of various nuclear receptors. Interestingly, a recent paper has described the conjugation of vitamin B6 to RIP140 (receptor interacting protein of 140 kDa), a protein that acts as a transcriptional corepressor of nuclear receptors. This post-translational modification increases the transcriptional repression of RIP140 and regulates its subcellular localization and its ability to interact with different protein partners. Finally, vitamin B6 is involved in the methyl donor cycle ant thus, some of the antitumor properties of vitamin B6 may involve an indirect effect on the level of DNA or histone methylation. All of these mechanistic and clinical data justify further studies to decipher the mechanism of action of vitamin B6 and its clinical interest in combination with molecules typically used in chemotherapy or hormonal therapy.

Epigenetic gene regulation contributes, together with genetic alterations, to cancer development and progression. In contrast to genetic disorders, the possibility of reversing epigenetic alterations has provided original targets for therapeutic application. In the last years, work has been focused on the pharmacological restoration of epigenetic regulation balance using epidrugs which yield hopes for novel strategy in cancer therapy. Histone acetylation and DNA methylation are epigenetic modifications which have been closely linked to the pathology of human cancers, and inhibitors of both enzyme classes for clinical use are at hands. Novel findings accumulated during the last years both in chemistry and biomedical applications give rise to new targeted treatments against cancer. Since their links with pathogenesis and progression of cancer were recognized, histone methyltransferases emerge as promising therapeutic targets in cancer treatment., (© 2011 médecine/sciences - Inserm / SRMS.)

Sepsis is defined as a systemic response to infection, characterized by an intense inflammatory response linked to coagulation activation and fibrinolysis inhibition, two processes which are intimately associated. In a field where mortality remains very high, administration of activated protein C, a physiological coagulation inhibitor with cytoprotective properties, has demonstrated its effectiveness and was able to reduce mortality. Protein C belongs to a system that involves plasma proteins and endothelial cell receptors. In addition to well documented effects on coagulation and fibrinolysis, activated protein C exhibits anti-inflammatory, anti-apoptotic but also anti-histone activities. Indeed, a recent study focusing on the cytoprotective effects of activated protein C showed that extracellular histones are released during severe sepsis and may participate in the pathophysiology of severe sepsis. These histones appear to be new targets of activated protein C., (© 2011 médecine/sciences - Inserm / SRMS.)

During meiosis, homologous reciprocal recombination events or crossing-over determine the genetic map and are known not to be randomly distributed in the genome. Recent studies in yeasts and mammals reveal some key features of the molecular mechanism involved in this distribution. Through different molecular processes, specific histone post-translational modifications are induced at specific genomic sites, called hotspots, where initiation of meiotic recombination takes place. These sites are some transcription promoters in S. cerevisiae or binding sites for transcription factors in S. pombe, where chromatin modifiers are recruited. In mammals, the sites are DNA sequences recognized by the PRDM9 protein which has the ability both to bind DNA and to induce the trimethylation of the lysine 4 of histone H3. The properties of the chromatin at these sites, and potentially the binding of additional factors, allow the recruitment of proteins involved in the formation of DNA double strand breaks that initiate meiotic recombination.

During their post-meiotic maturation, male germ cells undergo an extensive reorganization of their genome, during which histones become globally hyperacetylated, are then removed and progressively replaced by transition proteins and finally by protamines. The latter are known to tightly associate with DNA in the mature sperm cell. Although this is a highly conserved and fundamental biological process, which is a necessary prerequisite for the transmission of the male genome to the next generation, its molecular basis remains mostly unknown. We have identified several key factors involved in this process, and their detailed functional study has enabled us to propose the first model describing molecular mechanisms involved in post-meiotic male genome reprogramming. One of them, Bromodomain Testis Specific (BRDT), has been the focus of particular attention since it possesses the unique ability to specifically induce a dramatic compaction of acetylated chromatin. Interestingly, a mutation was found homozygous in infertile men which, according to our structural and functional studies, disrupts the function of the protein. A combination of molecular structural and genetic approaches has led to a comprehensive understanding of new major actors involved in the male genome reprogramming and transmission.

After fertilization in mammals, the genome of the newly formed embryo is first transcriptionally inactive. Development is then strictly dependent on the maternally inherited RNA and proteins present in the oocyte that were accumulated before ovulation during oocyte growth and maturation. The onset of transcription specific to the embryo, referred to as "embryonic genome activation (EGA)", is initiated later during development at various preimplantation stages according to species. Transcriptional activity can be underlined thanks to several approaches such as precursors incorporation in newly synthesized RNA and expression of reporter genes. These studies show that EGA is established in two phases: a "minor" one, first with reduced transcriptional activity and that does not require any specific transcription factor; second, a "major" phase with rapidly increasing transcription. Upon major activation, newly synthesized RNA/proteins are essential for further embryonic development. EGA is dependent on the availability and activity of the basal transcriptional machinery components but also on the structural modifications of the nuclei after fertilization. Indeed, during the first embryonic cycles, the maternal and paternal genome undergo intense chromatin remodeling that could be a key regulator of embryonic transcription.

The histones, that wrap the DNA to form the nucleosome core, are targeted by diverse post-translational modifications. How those modifications affect DNA accessibility and chromatin folding is a fundamental biological issue. Furthermore, tremendous amounts of data suggest that the loss of specific modifications as well as an inappropriate ectopic pattern of modifications at given loci contributes to the development of several human syndromes as well as cancers. In this review, we focus on the current knowledge of the regulation and impact of histone H4 lysine 16 acetylation on the genome. Recent discoveries highlight its crucial involvement in events such as transcription regulation, chromatin specialization, chromosome compaction and tumoral progression.

DNA methylation plays a pivotal role during development and carcinogenesis and is central to gene silencing. The recent characterization of the DNA methyltransferases--Dnmt- and their protein partners have helped to understand the molecular basis underlying methylation-mediated gene silencing and its involvement in cancer. These discoveries have important implications to the comprehension of transcriptional regulation but also to understand the molecular basis underlying tumorigenesis. Moreover, these studies open new ways towards an epigenetic therapy of cancer.

The methylation of 5'CpG 3' dinucleotides within genes creates potential targets for protein complexes that bind to methylated DNA sequences and to histone deacetylases (MBD-HDAC). This can lead to transcriptional repression by modification of chromatic. To test the importance of this repression in vivo and to determine when during development these epigenetic controls are placed on genes, two novel genes have been engineered by directed mutagenesis of the CpG-rich LacZ gene that are depleted of (LagZ) or completely lacking (LagoZ) CpG sequences. We report that the expression (transcriptional and translational) of the three genes is indistinguishable in transient assays in cleaving mouse embryos. Therefore, the complete absence of CpG sequences within three kilobases of coding sequence is compatible with its maintenance in the nucleus and with its expression. These molecules can now be used to study the ontogenesis of the CpG-dependent repressive system in intact organisms.

This paper summarizes the contradictory epidemiological data concerning the association between vegetal fibres intake and colorectal cancer incidence. The key to these discrepancies might reside in the different amounts and ratios of butyrate and other short chain fatty acids (SCFA) produced by colonic anaerobic bacteria during fermentation of fibers from different origins, wheat bran fibers being better producers and therefore more protective. Butyrate, an established histone deacetylase inhibitor, acts by favoring an active chromatin configuration of the P21WAF1/CIP1 gene which, as an inhibitor of cyclin-dependent protein-kinases, blocks the cell cycle.

During the cell cycle, chromatin undergoes structural changes associated with cellular functions such as DNA replication during the S phase or the transcriptional inactivation during metaphase. All levels of chromatin organization from the nucleosome to the loops attached to the scaffold are concerned by these changes. Biochemical or biophysical studies from 70's, as well as more recent studies using nondestructive in situ methods, that allow to obtain information at the individual cell level, tend to demonstrate a correlation between the condensation state of the chromatin and the position of the cell in the cycle. The majority of these studies confirm the existence of one single cycle of condensation-decondensation for the chromatin. These studies are discussed in the first part of this chapter. In the second part, the role of the cdc (cell division cycle) gene's products in the control of the cell cycle and in the regulation of the chromatin structure are analyzed.

During dog-fish spermiogenesis, 2 basic nuclear protein transitions occur: the first from histones to spermatid-specific proteins S1 and S2, the second leading to protamines. S1, the most abundant transition protein, is a polypeptide containing 87 residues (Mr = 11,179 Da) whereas S2, the minor transition protein, contains 80 residues (Mr = 9,726 Da). The 2 proteins are mainly characterized by an asymmetry of the molecule, a very high content of basic residues, a relatively high level of hydrophobic residues and a cluster of acidic residues in the carboxy-terminal quarter of the molecule. The 2 proteins are phosphorylated on serine residues and the degree of phosphorylation is relatively important in protein S1. The 2 transition proteins are structurally unrelated to testis histones or sperm protamines and cannot be considered either as their proteolytic degradation products or as their precursors.

The main progresses which occurred last years in the knowledge of chromatin, in its biochemical components, structure and organization levels, are briefly outlined. Inhibition of transcriptional activity is examined at the molecular, cellular and chromosomal levels. The different states of chromatin condensation according to physiopathological conditions are more particularly reviewed together with recent data on transcriptional regulation depending on histone and DNA modifications.

The muscular cells of regenerating limbs and of limbs in which regenerative power is restored, show an important decrease in the amount of cytophotometrically detected histones. This decrease is owing to the arginine rich fraction and to the lysine rich fraction. The muscular cells of irradiated limbs show a decrease in the amount of histones. This decrease is owing only to the arginine rich fraction and continues after the thirieth day of irradiation and amputation.

The effects of histone 2A and some polycations on microsomal carbamylphosphate:D-glucose phosphotransferase and glucose-6-phosphate phosphohydrolase activities (D-glucose-6-phosphate phosphohydrolase, EC 3.1.3.9), have been investigated. 1. Histone 2A and polycations activate the two enzymic activities. At a constant cation concentration, this activation increases with the number of cationic groups per molecule. 2. Activation by histone 2A is related to its fixation on microsomal membranes. This fixation varies with quantities of histones and pH. 3. The nature of the interactions between histones and microsomal membranes is shown to be electrostatic, probably between the cationic groups of histones and the anionic group of membranous lipids. 4. Kinetic analysis reveal that histone 2A increases the maximal reaction velocity but does not affect the apparent Michaelis constant values for the substrates. 5. The role played by the cationic groups of histone 2A on the microsomal glucose 6-phosphatase, is discussed.