Search

In mammals, X-chromosomal genes are expressed from a single copy since males (XY) possess a single X chromosome, while females (XX) undergo X inactivation. To compensate for this reduction in dosage compared with two active copies of autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation. However, the existence and mechanisms of X-to-autosome dosage compensation are still under debate. Here we show that X-chromosomal transcripts have fewer m6A modifications and are more stable than their autosomal counterparts. Acute depletion of m6A selectively stabilizes autosomal transcripts, resulting in perturbed dosage compensation in mouse embryonic stem cells. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m6A, indicating that mammalian dosage compensation is partly regulated by epitranscriptomic RNA modifications.

A two-year collective effort towards the reduction by 50% of the usage of 7 hazardous solvents (Green Chemistry Principle #5) within a large-scale industrial R&D organization.

Understanding the evolutionary and ecological roles of non-genetic inheritance is daunting due to the complexity and diversity of epigenetic mechanisms. We draw on precise insights from molecular structures and events to identify three general features of non-genetic inheritance systems that are central to broader investigations: (i) they are functionally interdependent with, rather than separate from, DNA sequence; (ii) each of these mechanisms is not uniform but instead varies phylogenetically and operationally; and (iii) epigenetic elements are probabilistic, interactive regulatory factors and not deterministic epi-alleles with defined genomic locations and effects. We explain each feature and offer research recommendations. Finally, we consider existing evolutionary models for non-genetic inheritance and present a new model that implements a unifying inherited gene regulation approach.

Confinement of the X chromosome to a territory for dosage compensation is a prime example of how subnuclear compartmentalization is used to regulate transcription at the megabase scale. In Drosophila melanogaster, two sex-specific non-coding RNAs (roX1 and roX2) are transcribed from the X chromosome. They associate with the male-specific lethal (MSL) complex1, which acetylates histone H4 lysine 16 and thereby induces an approximately twofold increase in expression of male X-linked genes2,3. Current models suggest that X-over-autosome specificity is achieved by the recognition of cis-regulatory DNA high-affinity sites (HAS) by the MSL2 subunit4,5. However, HAS motifs are also found on autosomes, indicating that additional factors must stabilize the association of the MSL complex with the X chromosome. Here we show that the low-complexity C-terminal domain (CTD) of MSL2 renders its recruitment to the X chromosome sensitive to roX non-coding RNAs. roX non-coding RNAs and the MSL2 CTD form a stably condensed state, and functional analyses in Drosophila and mammalian cells show that their interactions are crucial for dosage compensation in vivo. Replacing the CTD of mammalian MSL2 with that from Drosophila and expressing roX in cis is sufficient to nucleate ectopic dosage compensation in mammalian cells. Thus, the condensing nature of roX–MSL2CTD is the primary determinant for specific compartmentalization of the X chromosome in Drosophila. Dosage compensation in Drosophila involves nucleation of the dosage compensation complex at the X chromosome by MSL2 and the non-coding RNA roX.

Dans ses deux recueils de poésie The Boy from the Chemist is Here to See You (1998) et The Ice Age (2002), Paul Farley explore les dichotomies classiques opposant nature et culture, microcosme et macrocosme dans une écriture poétique novatrice qui définit un engagement éthique et façonne une relation à la terre qui prône une attention radicale à l'infime comme à l'infini. Cette étude interroge ce mode d'attention spécifique à travers lequel le poète ouvre une brèche dans la matière et explore les ténèbres pour y déceler la source du visible. La terre devient ainsi cette "pellicule obscure" (The Dark Film, titre d'un recueil de poèmes publié en 2012) sur laquelle le lecteur est invité à déchiffrer les traces d'une nature au sein de laquelle l'humain et le non-humain ne sauraient être dissociés. Au cœur d'une société déconnectée, obsédée par sa propre technicité, et où l'homme s'est coupé du monde sensible et des autres, Paul Farley redéfinit ainsi les modalités du visible en tissant ensemble le poétique et le politique et déploie une attention au monde qui est à la fois d'ordre esthétique et éthique.

Körperliche Aktivität ist ein Eckpfeiler im Diabetes-Management; es gibt jedoch nur wenige Evidenzsynthesen zum Zusammenhang zwischen körperlicher Aktivität und langfristigen diabetesbedingten schweren Komplikationen. Was „schlüssig“ scheint, konnte jetzt in einer großen Metaanalyse des Deutschen Diabetes-Zentrums (DDZ) als faktisch gegeben bewiesen werden 1.

Diploid organisms contain a maternal and a paternal genome complement that is thought to provide robustness and allow developmental progression despite genetic perturbations that occur in heterozygosity. However, changes affecting gene dosage from the chromosome down to the individual gene level possess a significant pathological potential and can lead to developmental disorders (DDs). This indicates that expression from a balanced gene complement is highly relevant for proper cellular and organismal function in eukaryotes. Paradoxically, gene and whole chromosome duplications are a principal driver of evolution, while heteromorphic sex chromosomes (XY and ZW) are naturally occurring aneuploidies important for sex determination. Here, we provide an overview of the biology of gene dosage at the crossroads between evolutionary benefit and pathogenicity during disease. We describe the buffering mechanisms and cellular responses to alterations, which could provide a common ground for the understanding of DDs caused by copy number alterations.

CRISPR knockout of msl-2 and epigenome analyses in Anopheles reveal that X chromosome dosage compensation in mosquitos and Drosophila is achieved by two different molecular mechanisms., Sex chromosomes induce potentially deleterious gene expression imbalances that are frequently corrected by dosage compensation (DC). Three distinct molecular strategies to achieve DC have been previously described in nematodes, fruit flies, and mammals. Is this a consequence of distinct genomes, functional or ecological constraints, or random initial commitment to an evolutionary trajectory? Here, we study DC in the malaria mosquito Anopheles gambiae. The Anopheles and Drosophila X chromosomes evolved independently but share a high degree of homology. We find that Anopheles achieves DC by a mechanism distinct from the Drosophila MSL complex–histone H4 lysine 16 acetylation pathway. CRISPR knockout of Anopheles msl-2 leads to embryonic lethality in both sexes. Transcriptome analyses indicate that this phenotype is not a consequence of defective X chromosome DC. By immunofluorescence and ChIP, H4K16ac does not preferentially enrich on the male X. Instead, the mosquito MSL pathway regulates conserved developmental genes. We conclude that a novel mechanism confers X chromosome up-regulation in Anopheles. Our findings highlight the pluralism of gene-dosage buffering mechanisms even under similar genomic and functional constraints.

Les récits de voyage Mani et Roumeli de Patrick Leigh Fermor rendent moins compte des années d’expérience de l’auteur en terre étrangère qu’ils n’invitent le lecteur à l’accompagner dans ses pérégrinations pour tenter de suivre le fil d’une méditation déambulatoire dans les montagnes de Grèce, lieu par excellence de la rencontre de l’humain et du non-humain où les déplacements physiques, culturels et linguistiques ré-enchantent notre vision de l’humanité. Découvrir et connaître le lieu dans ses particularités infimes, les hommes et la nature qui la peuplent, se conçoit comme un exploit, une victoire sur soi-même et sur un environnement souvent hostile, un privilège. Déployant un paysage littéraire clairement ancré dans les théories du sublime de Burke, et explorant conjointement, la matière physique et haptique du lieu, Patrick Leigh Fermor replace l’humain et le non-humain sur un pied d’égalité. Géographie physique et exploration métaphysique, description géologique et zoologique et écoute poétique se mêlent dans cette attention que Patrick Leigh Fermor prête au monde qui l’entoure. L’élan nomade de cette poésie de l’inattendu et de l’insaisissable laisse entendre la musique infime des formes de vie modestes et esquisse la possibilité d’une humanité nouvelle.

Self-renewal and differentiation of hematopoietic stem cells (HSCs) are orchestrated by the combinatorial action of transcription factors and epigenetic regulators. Here, we have explored the mechanism by which histone H4 lysine 16 acetyltransferase MOF regulates erythropoiesis. Single-cell RNA sequencing and chromatin immunoprecipitation sequencing uncovered that MOF influences erythroid trajectory by dynamic recruitment to chromatin and its haploinsufficiency causes accumulation of a transient HSC population. A regulatory network consisting of MOF, RUNX1, and GFI1B is critical for erythroid fate commitment. GFI1B acts as a Mof activator which is necessary and sufficient for cell type-specific induction of Mof expression. Plasticity of Mof-depleted HSCs can be rescued by expression of a downstream effector, Gata1, or by rebalancing acetylation via a histone deacetylase inhibitor. Accurate timing and dosage of Mof expression act as a rheostat for the feedforward transcription factor network that safeguards progression along the erythroid fate.

Haploinsufficiency and aneuploidy are two phenomena, where gene dosage alterations cause severe defects ultimately resulting in developmental failures and disease. One remarkable exception is the X chromosome, where copy number differences between sexes are buffered by dosage compensation systems. In Drosophila, the Male-Specific Lethal complex (MSLc) mediates upregulation of the single male X chromosome. The evolutionary origin and conservation of this process orchestrated by MSL2, the only male-specific protein within the fly MSLc, have remained unclear. Here, we report that MSL2, in addition to regulating the X chromosome, targets autosomal genes involved in patterning and morphogenesis. Precise regulation of these genes by MSL2 is required for proper development. This set of dosage-sensitive genes maintains such regulation during evolution, as MSL2 binds and similarly regulates mouse orthologues via Histone H4 lysine 16 acetylation. We propose that this gene-by-gene dosage compensation mechanism was co-opted during evolution for chromosome-wide regulation of the Drosophila male X., In Drosophila the Male-Specific Lethal complex (MSLc) mediates upregulation of the single male X chromosome. Here the authors provide evidence that MSL2 also targets autosomal genes required for proper development and that MSL2 binds and similarly regulates mouse orthologues.

Classic forms of 21-hydroxylase deficiency (21OHD) are usually diagnosed at birth by salt wasting or precocious puberty in male patients. Here we report the case of a 32-year-old male patient who presented with azoospermia and bilateral testicular tumors. He was referred to our endocrine unit after testicular surgery. His gonadotropins were undetectable. Liquid chromatography–tandem mass spectrometry revealed a high serum progesterone level, high 17-hydroxyprogesterone (17OHP) (255 ng/mL), and high levels of 17OHP metabolites, suggesting a classic form of 21OHD. His blood pressure was normal. Molecular analysis showed a homozygous large 21-hydroxylase gene (CYP21A2) conversion. Furthermore, an adrenal CT scan revealed voluminous, heterogeneous bilateral and asymmetric adrenal masses containing calcifications. Our case report illustrates the fact that a classic form of 21OHD can be diagnosed in late adulthood, manifested by azoospermia and large adrenal tumors, associated with elevated 17OHP., We describe a severe form of 21OHD diagnosed in late adulthood, in front of bilateral testicular tumors, azoospermia, and large bilateral adrenal masses, mimicking adrenocortical carcinoma.

This paper explores the subtle forms of Jon McGregor’s ethical commitment, through the photographic and cinematographic devices that haunt his fiction. Such devices play an important role in most of his works, but this paper focuses on his first novel, If Nobody Speaks of Remarkable Things (2002). The intermedial nature of the photographic practice is here brought to the fore by a narrative that deliberately weaves together the textual and the visual in order to resist the hegemonic vision that does away with the all too often unremarkable Other. I contend that the various photographs, taken and not taken, plead for a new poetic commitment that unsettles our vision by foregrounding new spaces of visibility.

International audience; Thyroid scintigraphy holds a key place in the etiologic workup of neonatal hypothyroidism. Routine screening for this disorder in maternity hospitals in industrialized countries, for nearly 40 years, has permitted early treatment and thereby helped to prevent its physical and mental complications. Neonatal hypothyroidism affects approximately 1 in 3000 births. The most common causes are abnormal thyroid gland development and defective hormone synthesis by an eutopic thyroid gland. The incidence of the latter has risen in recent years, for reasons that remain unclear. A thorough etiologic workup helps to determine the disease type. Current guidelines recommend thyroid imaging by means of ultrasound and scintigraphy. Ultrasound should be done by a practitioner trained to examine the cervical region of newborns, as the thyroid is very small and must be distinguished from the particular aspect of the “thyroid empty lodge.” Ultrasound lacks sensitivity for detecting small ectopic glands but is the gold standard for measuring thyroid dimensions. Scintigraphy provides an etiologic diagnosis in most cases. The two isotopes used in this setting are technetium-99m and iodine-123. The latter isotope gives more contrast and allows the perchlorate discharge test to be performed to detect abnormal iodide organification in the neonate with an eutopic thyroid. If scintigraphy cannot be performed during the neonatal period, a postponed procedure can be achieved after 3 years of age. Close cooperation between the nuclear medicine physician and the pediatric endocrinologist is crucial for timely and optimized scintigraphy.

Genome rearrangements that occur during evolution impose major challenges on regulatory mechanisms that rely on three-dimensional genome architecture. Here, we developed a scaffolding algorithm and generated chromosome-length assemblies from Hi-C data for studying genome topology in three distantly relatedDrosophilaspecies. We observe extensive genome shuffling between these species with one synteny breakpoint after approximately every six genes. A/B compartments, a set of large gene-dense topologically associating domains (TADs) and spatial contacts between high-affinity sites (HAS) located on the X chromosome are maintained over 40 million years, indicating architectural conservation at various hierarchies. Evolutionary conserved genes cluster in the vicinity of HAS, while HAS locations appear evolutionarily flexible, thus uncoupling functional requirement of dosage compensation from individual positions on the linear X chromosome. Therefore, 3D architecture is preserved even in scenarios of thousands of rearrangements highlighting its relevance for essential processes such as dosage compensation of the X chromosome.

Bruce Drexel’s narrative, which opens the first volume of The Avignon Quintet, Monsieur, paves the way for a trip down the lanes and memories of the past, preparing the reader to a textual backward journey. As he comes back to Avignon to attend the funeral of his friend, the travelling narrator is also setting out on a hidden quest which will enable him to measure the distance between reality and fiction, i.e., between his own memories of the past and their rewriting by the fictitious author Rob Sutcliffe. Exploring Sade’s hypotext therefore leads the reader into a spatial and temporal journey throughout which he discovers how Durrell resorts to Sade’s spatio-temporal architecture in order to suggest a spiritual vision of the self. The dismembered bodies of his characters do not serve to illustrate the fulfilment of jouissance but the dispersion of the ego and the birth of a new self. Annonçant un retour dans l’espace et dans le temps, le récit de Bruce Drexel qui ouvre le premier volume du Quintette d’Avignon, Monsieur, préfigure aussi un retour textuel. Revenant à Avignon pour l’enterrement de son ami, le narrateur voyageur poursuit aussi, chemin faisant, un parcours en creux qui lui permet de mesurer la distance qui sépare le réel de la fiction – c’est-à-dire le souvenir de son expérience passée, et sa retranscription par l’écrivain fictif Rob Sutcliffe. La descente dans l’hypotexte sadien prend ainsi la forme d’un long voyage au cœur de l’espace et de la mémoire au cours duquel le lecteur découvre comment Durrell se réapproprie l’économie du texte sadien dans une perspective résolument spiritualiste pour explorer, à travers les corps démembrés des personnages, non pas l’assouvissement de la jouissance, mais la dispersion de l’ego et l’émergence d’un nouveau sujet.

Confinement of the X chromosome to a territory for dosage compensation is a prime example of how subnuclear compartmentalization is used to regulate transcription at the megabase scale. In Drosophila melanogaster, two sex-specific non-coding RNAs (roX1 and roX2) are transcribed from the X chromosome. They associate with the male-specific lethal (MSL) complex

Self-renewal and differentiation of hematopoietic stem cells (HSCs) is orchestrated by the combinatorial function of transcription factors and epigenetic regulators. Here, we report the Histone H4 lysine 16 (H4K16) acetyl-transferase MOF is required for erythropoiesis. Single-cell-RNAseq of HSCs revealed that Mof influences erythroid trajectory and its haploinsufficiency causes the accumulation of a rare HSC population. ChIPseq and chromatin accessibility experiments in primary cells showed dynamic recruitment of MOF that regulates chromatin status. Genome-wide and functional data, revealed a regulatory network consisting of Mof, Gfi1b and Runx1 that is critical for erythroid fate. GFI1B binds to the Mof promoter and regulates its expression in a cell-specific manner. Plasticity of Mof-depleted HSCs can be rescued by expression of Gata1, or by rebalancing acetylation levels using a H4K16ac-selective HDAC-inhibitor. Collectively, these data unravel the mechanism and relevance of accurate timing and dosage of Mof expression as part of a feed-forward transcription factor network.