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Transient upregulation of IRF1 during exit from naive pluripotency confers viral protection

ABSTRACT: Stem cells intrinsically express a subset of genes which are normally associated with interferon stimulation and the innate immune response. However, expression of these interferon stimulated genes (ISG) in stem cells is independent from external stimuli such as viral infection. Here, we show that the interferon regulatory factor 1, Irf1, is directly controlled by the murine formative pluripotency gene regulatory network and transiently upregulated during the transition from naive to formative pluripotency. IRF1 binds to regulatory regions of a conserved set of ISGs and is required for their faithful expression upon exit from naive pluripotency. We show that in the absence of IRF1, cells exiting the naive pluripotent stem cell state are more susceptible to viral infection. Irf1 therefore acts as a link between the formative pluripotency network, regulation of innate immunity genes and defense against viral infections during formative pluripotency.

SUBMITTER: Mrs. Merrit Romeike

PROVIDER: S-SCDT-EMBOR-2022-55375V1 | biostudies-other |

REPOSITORIES: biostudies-other

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Transient upregulation of IRF1 during exit from naive pluripotency confers viral protection.

Project description:Stem cells intrinsically express a subset of genes which are normally associated with interferon stimulation and the innate immune response. However, the expression of these interferon-stimulated genes (ISG) in stem cells is independent from external stimuli such as viral infection. Here, we show that the interferon regulatory factor 1, Irf1, is directly controlled by the murine formative pluripotency gene regulatory network and transiently upregulated during the transition from naive to formative pluripotency. IRF1 binds to regulatory regions of a conserved set of ISGs and is required for their faithful expression upon exit from naive pluripotency. We show that in the absence of IRF1, cells exiting the naive pluripotent stem cell state are more susceptible to viral infection. Irf1 therefore acts as a link between the formative pluripotency network, regulation of innate immunity genes, and defense against viral infections during formative pluripotency.

| S-EPMC9442322 | biostudies-literature

Transient upregulation of IRF1 during the exit from naive pluripotency confers viral protection

Project description:IRF1 in exit from naive pluripotency

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Exit from Naive Pluripotency Induces a Transient X Chromosome Inactivation-like State in Males.

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| S-EPMC5989057 | biostudies-literature

Dynamic enhancer partitioning instructs activation of a growth-related gene during exit from naive pluripotency.

Project description:During early mammalian development, the chromatin landscape undergoes profound transitions. The Zdbf2 gene-involved in growth control-provides a valuable model to study this window: upon exit from naïve pluripotency and prior to tissue differentiation, it undergoes a switch from a distal to a proximal promoter usage, accompanied by a switch from polycomb to DNA methylation occupancy. Using a mouse embryonic stem cell (ESC) system to mimic this period, we show here that four enhancers contribute to the Zdbf2 promoter switch, concomitantly with dynamic changes in chromatin architecture. In ESCs, the locus is partitioned to facilitate enhancer contacts with the distal Zdbf2 promoter. Relieving the partition enhances proximal Zdbf2 promoter activity, as observed during differentiation or with genetic mutants. Importantly, we show that 3D regulation occurs upstream of the polycomb and DNA methylation pathways. Our study reveals the importance of multi-layered regulatory frameworks to ensure proper spatio-temporal activation of developmentally important genes.

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KLF4 Nuclear Export Requires ERK Activation and Initiates Exit from Naive Pluripotency.

Project description:Cooperative action of a transcription factor complex containing OCT4, SOX2, NANOG, and KLF4 maintains the naive pluripotent state; however, less is known about the mechanisms that disrupt this complex, initiating exit from pluripotency. We show that, as embryonic stem cells (ESCs) exit pluripotency, KLF4 protein is exported from the nucleus causing rapid decline in Nanog and Klf4 transcription; as a result, KLF4 is the first pluripotency transcription factor removed from transcription-associated complexes during differentiation. KLF4 nuclear export requires ERK activation, and phosphorylation of KLF4 by ERK initiates interaction of KLF4 with nuclear export factor XPO1, leading to KLF4 export. Mutation of the ERK phosphorylation site in KLF4 (S132) blocks KLF4 nuclear export, the decline in Nanog, Klf4, and Sox2 mRNA, and differentiation. These findings demonstrate that relocalization of KLF4 to the cytoplasm is a critical first step in exit from the naive pluripotent state and initiation of ESC differentiation.

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Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency.

Project description:The genome of pluripotent stem cells adopts a unique three-dimensional architecture featuring weakly condensed heterochromatin and large nucleosome-free regions. Yet, it is unknown whether structural loops and contact domains display characteristics that distinguish embryonic stem cells (ESCs) from differentiated cell types. We used genome-wide chromosome conformation capture and super-resolution imaging to determine nuclear organization in mouse ESC and neural stem cell (NSC) derivatives. We found that loss of pluripotency is accompanied by widespread gain of structural loops. This general architectural change correlates with enhanced binding of CTCF and cohesins and more pronounced insulation of contacts across chromatin boundaries in lineage-committed cells. Reprogramming NSCs to pluripotency restores the unique features of ESC domain topology. Domains defined by the anchors of loops established upon differentiation are enriched for developmental genes. Chromatin loop formation is a pervasive structural alteration to the genome that accompanies exit from pluripotency and delineates the spatial segregation of developmentally regulated genes.

| S-EPMC6327227 | biostudies-literature

Foxd3 Promotes Exit from Naive Pluripotency through Enhancer Decommissioning and Inhibits Germline Specification.

Project description:Following implantation, mouse epiblast cells transit from a naive to a primed state in which they are competent for both somatic and primordial germ cell (PGC) specification. Using mouse embryonic stem cells as an in vitro model to study the transcriptional regulatory principles orchestrating peri-implantation development, here we show that the transcription factor Foxd3 is necessary for exit from naive pluripotency and progression to a primed pluripotent state. During this transition, Foxd3 acts as a repressor that dismantles a significant fraction of the naive pluripotency expression program through decommissioning of active enhancers associated with key naive pluripotency and early germline genes. Subsequently, Foxd3 needs to be silenced in primed pluripotent cells to allow re-activation of relevant genes required for proper PGC specification. Our findings therefore uncover a cycle of activation and deactivation of Foxd3 required for exit from naive pluripotency and subsequent PGC specification.

| S-EPMC5048917 | biostudies-literature

MTCH2-mediated mitochondrial fusion drives exit from naive pluripotency in embryonic stem cells.

Project description:The role of mitochondria dynamics and its molecular regulators remains largely unknown during naïve-to-primed pluripotent cell interconversion. Here we report that mitochondrial MTCH2 is a regulator of mitochondrial fusion, essential for the naïve-to-primed interconversion of murine embryonic stem cells (ESCs). During this interconversion, wild-type ESCs elongate their mitochondria and slightly alter their glutamine utilization. In contrast, MTCH2-/- ESCs fail to elongate their mitochondria and to alter their metabolism, maintaining high levels of histone acetylation and expression of naïve pluripotency markers. Importantly, enforced mitochondria elongation by the pro-fusion protein Mitofusin (MFN) 2 or by a dominant negative form of the pro-fission protein dynamin-related protein (DRP) 1 is sufficient to drive the exit from naïve pluripotency of both MTCH2-/- and wild-type ESCs. Taken together, our data indicate that mitochondria elongation, governed by MTCH2, plays a critical role and constitutes an early driving force in the naïve-to-primed pluripotency interconversion of murine ESCs.

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| S-EPMC9701587 | biostudies-literature

Screening Genes Promoting Exit from Naive Pluripotency Based on Genome-Scale CRISPR-Cas9 Knockout.

Project description:Two of the main problems of stem cell and regenerative medicine are the exit of pluripotency and differentiation to functional cells or tissues. The answer to these two problems holds great value in the clinical translation of stem cell as well as regenerative medicine research. Although piling researches have revealed the truth about pluripotency maintenance, the mechanisms underlying pluripotent cell self-renewal, proliferation, and differentiation into specific cell lineages or tissues are yet to be defined. To this end, we took full advantage of a novel technology, namely, the genome-scale CRISPR-Cas9 knockout (GeCKO). As an effective way of introducing targeted loss-of-function mutations at specific sites in the genome, GeCKO is able to screen in an unbiased manner for key genes that promote exit from pluripotency in mouse embryonic stem cells (mESCs) for the first time. In this study, we successfully established a model based on GeCKO to screen the key genes in pluripotency withdrawal. Our strategies included lentiviral package and infection technology, lenti-Cas9 gene knockout technology, shRNA gene knockdown technology, next-generation sequencing, model-based analysis of genome-scale CRISPR-Cas9 knockout (MAGeCK analysis), GO analysis, and other methods. Our findings provide a novel approach for large-scale screening of genes involved in pluripotency exit and offer an entry point for cell fate regulation research.

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