Zfp281 orchestrates interconversion of pluripotent states by engaging Ehmt1 and Zic2

Mayer, Daniela; Stadler, Michael; Rittirsch, Melanie; Heß, Daniel; Lukonin, Ilya; Winzi, Maria; Smith, Austin; Buchholz, Frank; Betschinger, Joerg

doi:10.15252/embj.2019102591

Cited by 23 publications

(27 citation statements)

References 103 publications

(214 reference statements)

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“…Whereas Lin28a and Zfp281 bind more abundantly to chromatin in serum. Our results are in line with the role of Lin28a and Zfp281 in transitioning from naive to primed state of pluripotency (Mayer et al, 2020;Zhang et al, 2016). Interestingly, differential regulation of Zfp281 is only detectable by SPACE but not full proteome (Figure 4B).…”

Section: Comparative Space Of Mes Cells In Different Pluripotency Statessupporting

confidence: 88%

Chromatin-contact atlas reveals disorder-mediated protein interactions and moonlighting chromatin-associated RBPs

Rafiee

Zagalak

Sidorov

et al. 2020

Preprint

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Chromatin is composed of many proteins that mediate intermolecular transactions with the genome. Comprehensive knowledge of these components and their interactions is necessary for insights into gene regulation and other activities; however, reliable identification of chromatin-associated proteins remains technically challenging. Here, we present SPACE (Silica Particle Assisted Chromatin Enrichment), a stringent and straightforward chromatin-purification method that helps identify direct DNA-binders separately from chromatin-associated proteins. We demonstrate SPACE’s unique strengths in three experimental set-ups: the sensitivity to detect novel chromatin-associated proteins, the quantitative nature to measure dynamic protein use across distinct cellular conditions, and the ability to handle 10-25 times less starting material than competing methods. In doing so, we reveal an unforeseen scale of association between over 500 nuclear RNA-binding proteins (RBPs) with chromatin and DNA, providing new insights into their roles as important regulators of genome maintenance and chromatin composition. Applied to iPSC-derived neural precursors, we discover a new role for the amyotrophic lateral sclerosis (ALS)-causing Valosin Containing Protein (VCP) in recruiting DNA-damage components to chromatin, thus paving the way for molecular mechanistic insights into the disease. SPACE is a fast and versatile technique with many applications.

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Section: Comparative Space Of Mes Cells In Different Pluripotency Statessupporting

confidence: 88%

Chromatin-contact atlas reveals disorder-mediated protein interactions and moonlighting chromatin-associated RBPs

Rafiee

Zagalak

Sidorov

et al. 2020

Preprint

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“…Strikingly, Zfp281 and Csnk1a1 KO profiles at N24 showed similarity to the E4.5 epiblast on par with WT cells cultured in 2i (Fig 4D). The strong Zfp281 phenotype is consistent with an overt differentiation delay phenotype (Mayer et al , 2020). Overall, there was a good correlation between the in vitro differentiation delay and the similarity with pre‐implantation epiblast cells, and both the 2i and N24 KO transcriptomes that were more similar to the E4.5 epiblast exhibited stronger exit‐delay phenotypes in vitro (Figs 4C and D, and EV2A).…”

Section: Resultsmentioning

confidence: 53%

Cooperative genetic networks drive embryonic stem cell transition from naïve to formative pluripotency

et al. 2021

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In the mammalian embryo, epiblast cells must exit the naïve state and acquire formative pluripotency. This cell state transition is recapitulated by mouse embryonic stem cells (ESCs), which undergo pluripotency progression in defined conditions in vitro. However, our understanding of the molecular cascades and gene networks involved in the exit from naïve pluripotency remains fragmentary. Here, we employed a combination of genetic screens in haploid ESCs, CRISPR/Cas9 gene disruption, large‐scale transcriptomics and computational systems biology to delineate the regulatory circuits governing naïve state exit. Transcriptome profiles for 73 ESC lines deficient for regulators of the exit from naïve pluripotency predominantly manifest delays on the trajectory from naïve to formative epiblast. We find that gene networks operative in ESCs are also active during transition from pre‐ to post‐implantation epiblast in utero. We identified 496 naïve state‐associated genes tightly connected to the in vivo epiblast state transition and largely conserved in primate embryos. Integrated analysis of mutant transcriptomes revealed funnelling of multiple gene activities into discrete regulatory modules. Finally, we delineate how intersections with signalling pathways direct this pivotal mammalian cell state transition.

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“…At N24 several KOs, such as Zfp281, Tsc2, Smg5 and Smg6, retained strong similarity to the E4.5 epiblast (Figures 4C,E and S4A). Strikingly, Zfp281 KO profiles at N24 showed similarity to the E4.5 epiblast on par with WT cells cultured in 2i (Figures 4C and S4A), consistent with an overt differentiation delay phenotype (Mayer et al, 2020). Overall, there was a good correlation between the in vitro differentiation delay and the similarity with preimplantation epiblast cells: the N24 KO transcriptomes that were more similar to the E4.5 epiblast exhibited stronger exit-delay phenotypes ( Figure 4E, Figure S4B).…”

Section: The Regulatory Program For Pre-to Post-implantation Epiblastmentioning

confidence: 62%

Cooperative genetic networks drive a mammalian cell state transition

Lackner

Sehlke

Garmhausen

et al. 2020

Preprint

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AbstractIn the mammalian embryo, epiblast cells must exit their naïve state and acquire formative pluripotency. This cell state transition is recapitulated by mouse embryonic stem cells (ESCs), which undergo pluripotency progression in defined conditions in vitro. However, our understanding of the molecular cascades and gene-networks involved in the exit from naïve pluripotency remains fragmented. Here we employed a combination of genetic screens in haploid ESCs, CRISPR/Cas9 gene disruption, large-scale transcriptomics and computational systems-biology to delineate the regulatory circuits governing naïve state exit. Transcriptome profiles for 73 knockout ESC lines predominantly manifest delays on the trajectory from naive to formative epiblast. We find that gene networks operative in ESCs are active during transition from pre- to post-implantation epiblast in utero. We identified 374 naïve-associated genes tightly connected to epiblast state and largely conserved in human ESCs and primate embryos. Integrated analysis of mutant transcriptomes revealed funneling of multiple gene activities into discrete regulatory modules. Finally, we delineate how intersections with signaling pathways direct this pivotal mammalian cell state transition.

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Zfp281 orchestrates interconversion of pluripotent states by engaging Ehmt1 and Zic2

Cited by 23 publications

References 103 publications

Chromatin-contact atlas reveals disorder-mediated protein interactions and moonlighting chromatin-associated RBPs

Chromatin-contact atlas reveals disorder-mediated protein interactions and moonlighting chromatin-associated RBPs

Cooperative genetic networks drive embryonic stem cell transition from naïve to formative pluripotency

Cooperative genetic networks drive a mammalian cell state transition

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