ENS - Départment de biologie

Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner

Frédérique Godfroid — 2017-12-22T15:25:21Z

Morgane Sonia Thion, Donovan Low, Aymeric Silvin, Jinmiao Chen, Pauline Grisel, Jonas Schulte-Schrepping, Ronnie Blecher, Thomas Ulas, Paola Squarzoni, Guillaume Hoeffel, Fanny Coulpier, Eleni Siopi, Friederike Sophie David, Claus Scholz, Foo Shihui, Josephine Lum, Arlaine Anne Amoyo, Anis Larbi, Michael Poidinger, Anne Buttgereit, Pierre-Marie Lledo, Melanie Greter, Jerry Kok Yen Chan, Ido Amit, Marc Beyer, Joachim Ludwig Schultze, Andreas Schlitzer, Sven Pettersson, Florent Ginhoux, Sonia Garel.

Highlights

• Microglia undergo sequential phases of differentiation during development
• The maternal microbiome influences microglial properties during prenatal stages
• The absence of the microbiome has a sex- and time-specific impact on microglia
• Microbiome depletions have acute and long-term effects on microglial properties

Summary

Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally : microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.

More information

doi.org/10.1016/j.cell.2017.11.042

Nathalie Spassky, lauréate du Prix Camille Woringer 2017.Fondation pour la Recherche Médicale

Frédérique Godfroid — 2017-12-08T16:28:50Z

- 2017 / Carrousel

Terence Strick, lauréat du Prix Coups d'élan pour la Recherche Française 2017Fondation Bettencourt Schueller

Frédérique Godfroid — 2017-11-20T08:51:46Z

Améliorer les infrastructures et les conditions de travail des chercheurs en sciences de la vie
Le prix Coups d'élan pour la recherche française a été créé par la Fondation en 2000. En dix-huit ans, 62 laboratoires français et plus de 500 chercheurs ont bénéficié de ce prix.
Il est attribué chaque année à quatre équipes de recherche biomédicale publique, relevant de l'Inserm et de l'Institut des sciences biologiques du CNRS.

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Hélène Morlon, lauréate du Prix Irène Joliot-Curie 2017 "Jeune Femme scientifique"

Frédérique Godfroid — 2017-11-13T10:30:22Z

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Pierre Paoletti, lauréat du Grand Prix Lamonica de Neurologie 2017. Académie des Sciences

Frédérique Godfroid — 2017-11-07T14:52:22Z

- 2017 / Carrousel

Comparative epigenomics in the Brassicaceae reveals two evolutionarily conserved modes of PRC2-mediated gene regulation

Frédérique Godfroid — 2017-11-06T09:29:54Z

Abstract

Background :
Polycomb Repressive Complexes 2 (PRC2) are multi-protein chromatin modifiers that are evolutionarily conserved among eukaryotes and play key roles in the regulation of gene expression, notably through the trimethylation of lysine 27 of histone H3 (H3K27me3). Although PRC2-mediated gene regulation has been studied in many organisms, few studies have explored in depth the evolutionary conservation of PRC2 targets.
Results :
Here, we compare the H3K27me3 epigenomic profiles for the two closely related species Arabidopsis thaliana and Arabidopsis lyrata and the more distant species Arabis alpina, three Brassicaceae that diverged from each other within the past 24 million years. Using a robust set of gene orthologs present in the three species, we identify two classes of evolutionarily conserved PRC2 targets, which are characterized by either developmentally plastic or developmentally constrained H3K27me3 marking across species. Constrained H3K27me3 marking is associated with higher conservation of promoter sequence information content and higher nucleosome occupancy compared to plastic H3K27me3 marking. Moreover, gene orthologs with constrained H3K27me3 marking exhibit a higher degree of tissue specificity and tend to be involved in developmental functions, whereas gene orthologs with plastic H3K27me3 marking preferentially encode proteins associated with metabolism and stress responses. In addition, gene orthologs with constrained H3K27me3 marking are the predominant contributors to higher-order chromosome organization.
Conclusions :
Our findings indicate that developmentally plastic and constrained H3K27me3 marking define two evolutionarily conserved modes of PRC2-mediated gene regulation that are associated with distinct selective pressures operating at multiple scales, from DNA sequence to gene function and chromosome architecture.

More informations

Genome Biol. 2017 Oct 31 ;18(1):207. doi : 10.1186/s13059-017-1333-9.

Dual origin of enteric neurons in vagal Schwann cell precursors and the sympathetic neural crest

Frédérique Godfroid — 2017-10-27T15:07:47Z

Abstract

Most of the enteric nervous system derives from the “vagal” neural crest, lying at the level of somites 1–7, which invades the digestive tract rostro-caudally from the foregut to the hindgut. Little is known about the initial phase of this colonization, which brings enteric precursors into the foregut. Here we show that the “vagal crest” subsumes two populations of enteric precursors with contrasted origins, initial modes of migration, and destinations. Crest cells adjacent to somites 1 and 2 produce Schwann cell precursors that colonize the vagus nerve, which in turn guides them into the esophagus and stomach. Crest cells adjacent to somites 3–7 belong to the crest streams contributing to sympathetic chains : they migrate ventrally, seed the sympathetic chains, and colonize the entire digestive tract thence. Accordingly, enteric ganglia, like sympathetic ones, are atrophic when deprived of signaling through the tyrosine kinase receptor ErbB3, while half of the esophageal ganglia require, like parasympathetic ones, the nerve-associated form of the ErbB3 ligand, Neuregulin-1. These dependencies might bear relevance to Hirschsprung disease, with which alleles of Neuregulin-1 are associated.

Significance

The enteric nervous system of vertebrates arises mostly from a rostral portion of the neural crest, encapsulated by the term “vagal.” We show that the “vagal crest” is in fact a juxtaposition of two completely different types of cells : Schwann cell precursors associated with the vagus nerve, which provide esophageal neurons, and the rostral-most trunk crest, which also forms sympathetic ganglia and locally overshoots the aorta to colonize most of the gut. Moreover, in line with the known dependency of both Schwann cell precursors and trunk crest on the ErbB3 tyrosine receptor kinase and its ligand Neuregulin1, we discover that the enteric nervous system is also atrophic in ErbB3 mutants, with potential relevance to Hirschsprung disease, a congenital hypoganglionosis.

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doi : 10.1073/pnas.1710308114

Calibrated mitotic oscillator drives motile ciliogenesis

Frédérique Godfroid — 2017-10-19T08:46:33Z

Abstract :

Cell division and differentiation depend on massive and rapid organelle remodeling. The mitotic oscillator, centered on the Cdk1-APC/C axis, spatiotemporally coordinates this reorganization in dividing cells. Here, we discovered that non-dividing cells could also implement this mitotic clock-like regulatory circuit to orchestrate subcellular reorganization associated with differentiation. We probed centriole amplification in differentiating mouse brain multiciliated cells. These post-mitotic progenitors fine-tuned mitotic oscillator activity to drive the orderly progression of centriole production, maturation and motile ciliation while avoiding the mitosis commitment threshold. Insufficient Cdk1 activity hindered differentiation, whereas excessive activity accelerated differentiation yet drove post-mitotic progenitors into mitosis. Thus, post-mitotic cells can redeploy and calibrate the mitotic oscillator to uncouple cytoplasmic from nuclear dynamics for organelle remodeling associated with differentiation.

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Science. 2017 Oct 5. pii : eaan8311. doi : 10.1126/science.aan8311

DNA methylation dynamics during early plant life

Frédérique Godfroid — 2017-09-26T07:59:34Z

Abstract

• Background : Cytosine methylation is crucial for gene regulation and silencing of transposable elements in mammals and plants. While this epigenetic mark is extensively reprogrammed in the germline and early embryos of mammals, the extent to which DNA methylation is reset between generations in plants remains largely unknown.

• Results : Using Arabidopsis as a model, we uncovered distinct DNA methylation dynamics over transposable element sequences during the early stages of plant development. Specifically, transposable elements and their relics show invariably high methylation at CG sites but increasing methylation at CHG and CHH sites. This non-CG methylation culminates in mature embryos, where it reaches saturation for a large fraction of methylated CHH sites, compared to the typical 10–20% methylation level observed in seedlings or adult plants. Moreover, the increase in CHH methylation during embryogenesis matches the hypomethylated state in the early endosperm.
Finally, we show that interfering with the embryo-to-seedling transition results in the persistence of high CHH methylation levels after germination, specifically over sequences that are targeted by the RNA-directed DNA methylation (RdDM) machinery.

• Conclusion : Our findings indicate the absence of extensive resetting of DNA methylation patterns during early plant life and point instead to an important role of RdDM in reinforcing DNA methylation of transposable element sequences in every cell of the mature embryo. Furthermore, we provide evidence that this elevated RdDM activity is a specific property of embryogenesis.

• Keywords : DNA methylation, RdDM, Transposable elements, Embryogenesis, Embryo-seedling transition.

More information here

Bouyer et al. Genome Biology.
doi 10.1186/s13059-017-1313-0.

Loss of the canonical spindle orientation function in the Pins/LGN homolog AGS3.

Frédérique Godfroid — 2017-08-29T16:33:33Z

Abstract
In many cell types, mitotic spindle orientation relies on the canonical "LGN complex" composed of Pins/LGN, Mud/NuMA, and Gαi subunits. Membrane localization of this complex recruits motor force generators that pull on astral microtubules to orient the spindle. Drosophila Pins shares highly conserved functional domains with its two vertebrate homologs LGN and AGS3. Whereas the role of Pins and LGN in oriented divisions is extensively documented, involvement of AGS3 remains controversial. Here, we show that AGS3 is not required for planar divisions of neural progenitors in the mouse neocortex. AGS3 is not recruited to the cell cortex and does not rescue LGN loss of function. Despite conserved interactions with NuMA and Gαiin vitro, comparison of LGN and AGS3 functional domains in vivo reveals unexpected differences in the ability of these interactions to mediate spindle orientation functions. Finally, we find that Drosophila Pins is unable to substitute for LGN loss of function in vertebrates, highlighting that species-specific modulations of the interactions between components of the Pins/LGN complex are crucial in vivo for spindle orientation.

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EMBO Rep. 2017 Jul 6. pii : e201643048. doi : 10.15252/embr.201643048.