Cell cycle regulators control mesoderm specification in human pluripotent stem cells

Yiangou, Loukia; Grandy, Rodrigo A.; Sinha, Sanjay; Vallier, Ludovic

doi:10.1101/632307

Cited by 7 publications

(6 citation statements)

References 51 publications

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“…We hypothesize that this strategy could facilitate rapid switching of methylation states that may be required to eliminate this modification efficiently during early cell fate transitions. For instance, active regulation may support rapid changes in cell cycle-dependent control that are required for the exit from pluripotency towards the early germ layers 48,49 . Simultaneously, these activities would also enable robust activation upon exposure to the appropriate differentiation signals.…”

Section: Discussionmentioning

confidence: 99%

TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers

et al. 2020

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Mammalian cells stably maintain high levels of DNA methylation despite expressing both positive (DNMT3A/B) and negative (TET1-3) regulators. Here, we analyzed the independent and combined effects of these regulators on the DNA methylation landscape using a panel of knockout human embryonic stem cell (ESC) lines. The greatest impact on global methylation levels was observed in DNMT3-deficient cells, including reproducible focal demethylation at thousands of normally methylated loci. Demethylation depends on TET expression and occurs only when both DNMT3s are absent. Dynamic loci are enriched for hydroxymethylcytosine and overlap with subsets of putative somatic enhancers that are methylated in ESCs and can be activated upon differentiation. We observe similar dynamics in mouse ESCs that were less frequent in epiblast stem cells (EpiSCs) and scarce in somatic tissues, suggesting a conserved pluripotency-linked mechanism. Taken together, our data reveal tightly regulated competition between DNMT3s and TETs at thousands of somatic regulatory sequences within pluripotent cells.

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Section: Discussionmentioning

confidence: 99%

TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers

et al. 2020

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“…CDK1 also appears to be necessary for EHT, and for balanced HPC differentiation and survival. Of note, CDKs are known to be involved in a variety of non-canonical functions such as transcriptional control and cell fate decision (39, 42, 43, 44, 45, 68). Accordingly, our results showed that the activation of CDK4/6 and CDK1 is required during EHT.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Endothelial-to-Haematopoietic Transition at the Single Cell Level identifies Cell Cycle Regulation as a Driver of Differentiation

Canu

Athanasiadis

Grandy

et al. 2020

Preprint

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Haematopoietic stem cells (HSC) first arise during development in the aorta-gonad-mesonephros (AGM) region of the embryo from a population of haemogenic endothelial cells which undergo endothelial-to-haematopoietic transition (EHT). Despite the progress achieved in recent years, the molecular mechanisms driving EHT are still poorly understood, especially in human where the AGM region is not easily accessible. In this study, we took advantage of a human pluripotent stem cell (hPSC) differentiation system and single-cell transcriptomics to recapitulate EHT in vitro and uncover mechanisms by which the haemogenic endothelium generates early haematopoietic cells. We show that most of the endothelial cells reside in a quiescent state and progress to the haematopoietic fate within a defined time window, within which they need to re-enter into the cell cycle. If cell cycle is blocked, haemogenic endothelial cells lose their EHT potential and adopt a non-haemogenic identity. Furthermore, we demonstrated that CDK4/6 and CDK1 play a key role not only in the transition but also in allowing haematopoietic progenitors to establish their full differentiation potential. Therefore, we propose a direct link between the molecular machineries that control cell cycle progression and EHT.

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“…Definitive endoderm differentiation was induced according to ( Yiangou et al, 2019 ). Cells were cultured in CDM-PVA supplemented with 100 ng/ml Activin A (produced in house), 80 ng/ml FGF2 (produced in house), 10 ng/ml BMP4 (R&D Systems), 10 µM LY294002 (Promega) and 3uM CHIR99021 for one day, with CHIR99021 omitted on the second day.…”

Section: Methodsmentioning

confidence: 99%

Differential regulation of lineage commitment in human and mouse primed pluripotent stem cells by the nucleosome remodelling and deacetylation complex

et al. 2020

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Cell cycle regulators control mesoderm specification in human pluripotent stem cells

Abstract: Mesoderm is one of the three germ layers produced during gastrulation from which muscle, bones, kidneys and the cardiovascular system

Cited by 7 publications

References 51 publications

TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers

TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers

Analysis of Endothelial-to-Haematopoietic Transition at the Single Cell Level identifies Cell Cycle Regulation as a Driver of Differentiation

Differential regulation of lineage commitment in human and mouse primed pluripotent stem cells by the nucleosome remodelling and deacetylation complex

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