The trophectoderm acts as a niche for the inner cell mass through C/EBPα-regulated IL-6 signaling

Gene regulation; Somatic cell reprogramming; TrophectodermRegulación de genes; Reprogramación de células somáticas; TrofoectodermoRegulació de gens; Reprogramació de cèl·lules somàtiques; TrofectodermaIL-6 has been shown to be required for somatic cell reprogramming into induced pluripotent stem cells (iPSCs). However, how Il6 expression is regulated and whether it plays a role during embryo development remains unknown. Here, we describe that IL-6 is necessary for C/EBPα-enhanced reprogramming of B cells into iPSCs but not for B cell to macrophage transdifferentiation. C/EBPα overexpression activates both Il6 and Il6ra genes in B cells and in PSCs. In embryo development, Cebpa is enriched in the trophectoderm of blastocysts together with Il6, while Il6ra is mostly expressed in the inner cell mass (ICM). In addition, Il6 expression in blastocysts requires Cebpa. Blastocysts secrete IL-6 and neutralization of the cytokine delays the morula to blastocyst transition. The observed requirement of C/EBPα-regulated IL-6 signaling for pluripotency during somatic cell reprogramming thus recapitulates a physiologic mechanism in which the trophectoderm acts as niche for the ICM through the secretion of IL-6.We thank C. Berenguer for help with B cell reprogramming and bone marrow collection; S. Nakagawa and B. Pernaute for advice on pre-implantation embryo culture and manipulation, and Kyle M. Loh for his valuable discussions; the flow cytometry and microscopy units of UPF-CRG for technical assistance; the CRG genomics core facility for sequencing and Graf laboratory members for critical discussions. Work in the laboratory of T.G. was supported by the Spanish Ministry of Economy, Industry and Competitiveness (Plan Estatal PID2019-109354GB-I00), the CRG, AGAUR (SGR 726), and a European Research Council Synergy grant (4D-Genome). M.P.-C. was supported by an FPI fellowship (BES-2016-076900). Work in the laboratory of M.S. was funded by the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (SAF2017-82613-R), ERC (ERC-2014-AdG/669622), la Caixa Foundation, and Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement of Catalonia (Grup de Recerca consolidat 2017 SGR 282)

The trophectoderm acts as a niche for the inner cell mass through C/EBPα-regulated IL-6 signaling

IL-6 has been shown to be required for somatic cell reprogramming into induced pluripotent stem cells (iPSCs). However, how Il6 expression is regulated and whether it plays a role during embryo development remains unknown. Here, we describe that IL-6 is necessary for C/EBPα-enhanced reprogramming of B cells into iPSCs but not for B cell to macrophage transdifferentiation. C/EBPα overexpression activates both Il6 and Il6ra genes in B cells and in PSCs. In embryo development, Cebpa is enriched in the trophectoderm of blastocysts together with Il6, while Il6ra is mostly expressed in the inner cell mass (ICM). In addition, Il6 expression in blastocysts requires Cebpa. Blastocysts secrete IL-6 and neutralization of the cytokine delays the morula to blastocyst transition. The observed requirement of C/EBPα-regulated IL-6 signaling for pluripotency during somatic cell reprogramming thus recapitulates a physiologic mechanism in which the trophectoderm acts as niche for the ICM through the secretion of IL-6.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved

Estimer l’âge biologique à partir du transcriptome pour étudier l’impact intergénérationnel des phéromones sur les dynamiques d’expression génique chez l’embryon de C. elegans

The environment influences not only the behavior and physiology of an organism, but can also impact its descendents. In the nematode model C. elegans, perception of social cues (pheromones) elicits such intergenerational effects, notably increasing generation time of the progeny. Here, I characterize the molecular changes in embryos caused by parental exposure to pheromone by profiling gene expression in single individuals.To achieve this, I first developed a robust computational method that infers age from the transcriptome in diverse organisms and sample types, makes it possible to detect and correct for developmental bias in gene expression data, and allows us to bypass synchronization and staging challenges for embryo collection. Then, I adapted experimental techniques used for sorting and profiling single cells to single embryos in order to improve throughput, revealing great potential for accessible and cost-efficient studies at large scale. Armed with these methods, I could then profile genome-wide gene expression of single individuals across embryo development in the progeny of pheromone-exposed and control parents. I show that gene expression of the developing nervous system and sensory organs are influenced by parental neuronal perception of the environment, likely changing how progeny will experience their own surroundings.L’environnement n’influence pas seulement le comportement et la physiologie d’un organisme, mais peut également avoir un impact sur sa descendance. Dans le nématode modèle C. elegans, la perception de l’environnement social (phéromones) déclenche de tels effets intergénérationnels, augmentant notamment le temps de génération de la progéniture. Dans mes travaux, je caractérise les changements moléculaires dans les embryons causés par l’exposition des parents aux phéromones en profilant l’expression des gènes à l’échelle de l’individu.Pour y parvenir, j’ai d’abord développé une méthode computationnelle robuste capable d’estimer l’âge à partir du transcriptome dans divers organismes et types d’échantillons, qui permet de détecter et de corriger les biais liés au développement dans les données d’expression génique, et nous permet de contourner les défis de synchronisation et de stadification pour la collecte des embryons. J’ai ensuite adapté des techniques expérimentales initialement utilisées pour trier et profiler les cellules uniques (single-cell) aux embryons pour permettre un haut débit, révélant un important potentiel pour mener des études à grande échelle de manière accessible et à moindre coût. Armé de ces méthodes, j’ai ensuite pu profiler l’expression des gènes d’individus uniques à l’échelle du génome tout au long du développement de l’embryon, provenant de parents exposés aux phéromones et de témoins. Je montre que l’expression génique du système nerveux et des organes sensoriels est influencée au cours de leur développement par la perception neuronale de l’environnement des parents, ce qui change certainement la manière dont la progéniture percevra son propre environnement

Estimer l’âge biologique à partir du transcriptome pour étudier l’impact intergénérationnel des phéromones sur les dynamiques d’expression génique chez l’embryon de C. elegans

The environment influences not only the behavior and physiology of an organism, but can also impact its descendents. In the nematode model C. elegans, perception of social cues (pheromones) elicits such intergenerational effects, notably increasing generation time of the progeny. Here, I characterize the molecular changes in embryos caused by parental exposure to pheromone by profiling gene expression in single individuals.To achieve this, I first developed a robust computational method that infers age from the transcriptome in diverse organisms and sample types, makes it possible to detect and correct for developmental bias in gene expression data, and allows us to bypass synchronization and staging challenges for embryo collection. Then, I adapted experimental techniques used for sorting and profiling single cells to single embryos in order to improve throughput, revealing great potential for accessible and cost-efficient studies at large scale. Armed with these methods, I could then profile genome-wide gene expression of single individuals across embryo development in the progeny of pheromone-exposed and control parents. I show that gene expression of the developing nervous system and sensory organs are influenced by parental neuronal perception of the environment, likely changing how progeny will experience their own surroundings.L’environnement n’influence pas seulement le comportement et la physiologie d’un organisme, mais peut également avoir un impact sur sa descendance. Dans le nématode modèle C. elegans, la perception de l’environnement social (phéromones) déclenche de tels effets intergénérationnels, augmentant notamment le temps de génération de la progéniture. Dans mes travaux, je caractérise les changements moléculaires dans les embryons causés par l’exposition des parents aux phéromones en profilant l’expression des gènes à l’échelle de l’individu.Pour y parvenir, j’ai d’abord développé une méthode computationnelle robuste capable d’estimer l’âge à partir du transcriptome dans divers organismes et types d’échantillons, qui permet de détecter et de corriger les biais liés au développement dans les données d’expression génique, et nous permet de contourner les défis de synchronisation et de stadification pour la collecte des embryons. J’ai ensuite adapté des techniques expérimentales initialement utilisées pour trier et profiler les cellules uniques (single-cell) aux embryons pour permettre un haut débit, révélant un important potentiel pour mener des études à grande échelle de manière accessible et à moindre coût. Armé de ces méthodes, j’ai ensuite pu profiler l’expression des gènes d’individus uniques à l’échelle du génome tout au long du développement de l’embryon, provenant de parents exposés aux phéromones et de témoins. Je montre que l’expression génique du système nerveux et des organes sensoriels est influencée au cours de leur développement par la perception neuronale de l’environnement des parents, ce qui change certainement la manière dont la progéniture percevra son propre environnement

Real age prediction from the transcriptome with RAPToR

International audienc

Management of Emergency Electroconvulsive Therapy in the Intensive Care Unit for Life-Threatening Psychiatric Conditions: A Case Series

International audienceCatatonia can lead to severe complications and may be lethal but is often underdiagnosed. The clinical presentation can be similar to coma. In these situations, electroconvulsive therapy (ECT) can be used as first-line treatment to enable extubation, recovery of autonomy, and rapid discharge from intensive care. We report 4 cases of patients hospitalized in the intensive care unit with comatose clinical presentation and life-threatening condition caused by catatonia. All patients received ECT sessions, after which the catatonic symptoms partially or fully remitted. We discuss the clinical identification, general considerations, ECT feasibility, and parameters in the intensive care unit, as well as the differential diagnosis, drug precautions, and prevention concerns

Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity

Here, we describe how the speed of C/EBPα-induced B cell to macrophage transdifferentiation (BMT) can be regulated, using both mouse and human models. The identification of a mutant of C/EBPα (C/EBPαR35A) that greatly accelerates BMT helped to illuminate the mechanism. Thus, incoming C/EBPα binds to PU.1, an obligate partner expressed in B cells, leading to the release of PU.1 from B cell enhancers, chromatin closing and silencing of the B cell program. Released PU.1 redistributes to macrophage enhancers newly occupied by C/EBPα, causing chromatin opening and activation of macrophage genes. All these steps are accelerated by C/EBPαR35A, initiated by its increased affinity for PU.1. Wild-type C/EBPα is methylated by Carm1 at arginine 35 and the enzyme’s perturbations modulate BMT velocity as predicted from the observations with the mutant. Increasing the proportion of unmethylated C/EBPα in granulocyte/macrophage progenitors by inhibiting Carm1 biases the cell’s differentiation toward macrophages, suggesting that cell fate decision velocity and lineage directionality are closely linked processes