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JMJD3 and UTX Determine Fidelity and Lineage Specification of Human Neural Progenitor Cells [ATAC-seq]

ABSTRACT: Neurogenesis entails a highly orchestrated process from pluripotent to neural cell fates including progenitors (NPCs) and various neural subtypes. However, the precise epigenetic mechanisms underlying the fate decision remain poorly understood. Here, we deleted KDM6s (JMJD3 or/and UTX), the demethylases for H3K27me3, in human embryonic stem cells (hESCs) and show that their deletion does not impede NPC generation from hESCs. However, KDM6-deficient NPCs exhibit poor proliferation and fail to become neurons and glia. Mechanistically, KDM6 deficiency leads to H3K27me3 accumulation and blockade of DNA accessibility at loci essential for neurogenesis, thus hinder the fate transition from NPCs to neural subtypes. Our findings uncover an essential role of KDM6s in neurogenesis and highlight the contribution of individual epigenetic regulators in specifying lineage fidelity and fate decision during human development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118988 | GEO | 2019/12/02

REPOSITORIES: GEO

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Project description:Exposure to lead (Pb) during childhood can result in learning disabilities and behavioral problems. Although described in animal models, whether Pb exposure also alters neuronal differentiation in the developing brains of exposed children is unknown. Here, we investigated the effects of physiologically relevant concentrations of Pb (from 0.4 to 1.9 M-BM-5M or 0 to 40M-BM-5g/dl) on the capacity of human embryonic stem cells (hESCs) to progress to a neuronal fate. We found that neither acute nor chronic exposure to Pb prevented hESCs from generating neural precursor cells (NPCs). NPCs derived from hESCs chronically exposed to 1.9 M-BM-5M or 40M-BM-5g/dl Pb throughout the neural differentiation process generated 2.5 times more TUJ1-positive neurons than those derived from control hESCs. Pb exposure of hESCs during the stage of neural rosette formation resulted in a significant decrease in the expression levels of the neural marker genes PAX6 and MSI1. Furthermore, the resulting NPCs differentiated into neurons with shorter neurites and less branching than control neurons, as assessed by Sholl analysis. DNA methylation studies of control, acutely treated hESCs and NPCs derived from chronically exposed hESCs using the Illumina HumanMethylation450 BeadChipM-BM-. demonstrated that Pb exposure induced changes in the methylation status of genes involved in neurogenetic signaling pathways. In summary, our study shows that exposure to Pb subtly alters the neuronal differentiation of exposed hESCs and that these changes could be partly mediated by modifications in the DNA methylation status of genes crucial to brain development. We analyzed the methylation profile of undifferentiated (n=2 independent experiments) and differentiating (n=2 independent experiments) human embryonic stem cells (hESCs) acutely exposed to losed to lead (Pb) and neural precursor cells derived from hESCs chronically exposed to Pb throughout the neural differentiation process (n=3 independent experiments).

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JMJD3 and UTX Determine Fidelity and Lineage Specification of Human Neural Progenitor Cells [ATAC-seq]

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