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

Developmental biology; Gene regulation; Transcription factorBiologia del desenvolupament; Regulació gènica; Factor de transcripcióBiología del desarrollo; Regulación génica; Factor de transcripciónHere, 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.TG was supported by the Center for Genomic Regulation, Barcelona, the Spanish Ministry of Economy, Industry and Competitiveness, (Plan Estatal PID2019-109354GB-100), AGAUR (SGR 006713) and the 4D-Genome European Research Council Synergy grant. KSZ was supported by the NIH grant R01GM36477. We have used ChatGPT to improve parts of the text

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

Methylation of a lineage-instructive transcription factor acts as a cell fate switch

Lineage-instructive transcription factors orchestrate cell fate decisions by regulating gene expression programs. However, how their function is regulated throughout development is poorly understood. C/EBPα is a transcription factor that has been shown to play a key role in several cell fate decisions of several tissues, including myelopoiesis, adipogenesis and early embryo development. The protein arginine methyltransferase Carm1 has also been described to play a role in cell specification during various developmental processes, but a connection to C/EBPα has not been established. In this Thesis, we investigated the link between the two proteins in cell fate decisions. We found that arginine 35 of C/EBPα is a key target of Carm1 methylation, and that this post-translational modification alters the biological properties of the factor and acts as a cell fate switch during myelopoiesis, adipogenesis and the first cell fate decision between pluripotency and trophectoderm in early embryos.Los factores de transcripción instructores de linaje orquestan decisiones de identidad celular a través de la regulación de programas de expresión génica. Sin embargo, cómo su función está regulada durante el desarrollo todavía se desconoce. C/EBPα es un factor de transcripción que juega un papel clave en varias decisiones de identidad celular, incluyendo mielopoiesis, adipogénesis y el desarrollo embrionario temprano. La metiltransferasa de argininas Carm1 también está involucrada en los mismos procesos, pero todavía no se ha descrito una posible conexión con C/EBPα. En esta Tesis, hemos investigado la conexión entre éstas dos proteínas en decisiones de identidad celular. Hemos descubierto que la arginina 35 de C/EBPα es un blanco clave para la metilación por Carm1, y está modificación postraduccional altera las propiedades biológicas del factor y actúa como un interruptor de identidad celular en mielopoiesis, adipogénesis y en la primera decisión entre pluripotencia y trofectodermo en el embrión

The transcription factor code: a beacon for histone methyltransferase docking

Histone methylation is required for the establishment and maintenance of gene expression patterns that determine cellular identity, and its perturbation often leads to aberrant development and disease. Recruitment of histone methyltransferases (HMTs) to gene regulatory elements (GREs) of developmental genes is important for the correct activation and silencing of these genes, but the drivers of this recruitment are largely unknown. Here we propose that lineage-instructive transcription factors (Lin-TFs) act as general recruiters of HMT complexes to cell type-specific GREs through protein-protein interactions. We also postulate that the specificity of these interactions is dictated by Lin-TF post-translational modifications (PTMs), which act as a 'transcription factor code' that can determine the directionality of cell fate decisions during differentiation and development

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

From research to rapid response: mass COVID-19 testing by volunteers at the Centre for Genomic Regulation

The COVID-19 pandemic has posed and is continuously posing enormous societal and health challenges worldwide. The research community has mobilized to develop novel projects to find a cure or a vaccine, as well as to contribute to mass testing, which has been a critical measure to contain the infection in several countries. Through this article, we share our experiences and learnings as a group of volunteers at the Centre for Genomic Regulation (CRG) in Barcelona, Spain. As members of the ORFEU project, an initiative by the Government of Catalonia to achieve mass testing of people at risk and contain the epidemic in Spain, we share our motivations, challenges and the key lessons learnt, which we feel will help better prepare the global society to address similar situations in the future.The ORFEU program was created by the Catalan Enterprise and Knowledge Department with the Department of Health and funded by the Government of Catalonia, who trusted the expertise of research institutes to add value to the health system during the pandemic. We also extend our thanks to the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa, the CERCA Programme / Generalitat de Catalunya, the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement, and the co-financing by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program. We acknowledge support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, to the EMBL partnership and to the Co-financing with funds from the European Regional Development Fund corresponding to the Programa Operativo FEDER Plurirregional de España (POPE) 2014-2020. We acknowledge also support of the Centro de Excelencia Severo Ochoa and the Generalitat de Catalunya through the CERCA Programme, through Departament de Salut and Departament d’Empresa i Coneixement and the Co-financing with funds from the European Regional Development Fund by the Secretaria d’Universitats i Recerca corresponding to the Programa Operatiu FEDER de Catalunya 2014-202