CHD8 safeguards early neuroectoderm differentiation in human ESCs and protects from apoptosis during neurogenesis

Ding, Song; Lan, Xianchun; Meng, Yajing; Yan, Chenchao; Li, Mao; Li, Xiang; Chen, Jian; Jiang, Wei

doi:10.1038/s41419-021-04292-5

Cited by 9 publications

(4 citation statements)

References 62 publications

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“…The cell cycle analysis was performed according to a previous work 64 . In brief, one million single cells were fixed in 75% ethanol at 4 °C overnight.…”

Section: Methodsmentioning

confidence: 99%

PCGF6 controls neuroectoderm specification of human pluripotent stem cells by activating SOX2 expression

et al. 2022

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Polycomb group (PcG) proteins are known to repress developmental genes during embryonic development and tissue homeostasis. Here, we report that PCGF6 controls neuroectoderm specification of human pluripotent stem cells (PSCs) by activating SOX2 gene. Human PSCs with PCGF6 depletion display impaired neuroectoderm differentiation coupled with increased mesendoderm outcomes. Transcriptome analysis reveals that de-repression of the WNT/β-catenin signaling pathway is responsible for the differentiation of PSC toward the mesendodermal lineage. Interestingly, PCGF6 and MYC directly interact and co-occupy a distal regulatory element of SOX2 to activate SOX2 expression, which likely accounts for the regulation in neuroectoderm differentiation. Supporting this notion, genomic deletion of the SOX2-regulatory element phenocopies the impaired neuroectoderm differentiation, while overexpressing SOX2 rescues the neuroectoderm phenotype caused by PCGF6-depletion. Together, our study reveals that PCGF6 can function as lineage switcher between mesendoderm and neuroectoderm in human PSCs by both suppression and activation mechanisms.

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“…The cell cycle analysis was performed according to a previous work 64 . In brief, one million single cells were fixed in 75% ethanol at 4 °C overnight.…”

Section: Methodsmentioning

confidence: 99%

PCGF6 controls neuroectoderm specification of human pluripotent stem cells by activating SOX2 expression

et al. 2022

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“…Previous studies on Chd8 -mutant mice and human neurons suggested multiple mechanisms that may underlie CHD8-related brain deficits ( Sugathan et al, 2014 ; Cotney et al, 2015 ; Wang et al, 2015 ; Breuss and Gleeson, 2016 ; Durak et al, 2016 ; Katayama et al, 2016 ; Gompers et al, 2017 ; Platt et al, 2017 ; Wang et al, 2017 ; Andreae and Basson, 2018 ; Jung et al, 2018 ; Suetterlin et al, 2018 ; Wade et al, 2018 ; Xu et al, 2018 ; Zhao et al, 2018 ; Hulbert et al, 2020 ; Jimenez et al, 2020 ; Sood et al, 2020 ; Cherepanov et al, 2021 ; Ding et al, 2021 ; Ellingford et al, 2021 ; Hurley et al, 2021 ; Kawamura et al, 2021 ; Kweon et al, 2021 ; Weissberg and Elliott, 2021 ; Chen et al, 2022 ; Coakley-Youngs et al, 2022 ; Dong et al, 2022 ; Haddad Derafshi et al, 2022 ; Jimenez et al, 2022 ; Kerschbamer et al, 2022 ; Lee et al, 2022 ; Paulsen et al, 2022 ; Thudium et al, 2022 ; Tu et al, 2022 ; Villa et al, 2022 ; Yu et al, 2022 ; Hayot et al, 2023 ). However, mechanisms underlying the male–female differences in CHD8-related ASD are poorly understood ( Jung et al, 2018 ; Cherepanov et al, 2021 ; Yu et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Age-differential sexual dimorphisms in CHD8-S62X-mutant mouse synapses and transcriptomes

Lee

Kweon²,

Kang³

et al. 2023

Front. Mol. Neurosci.

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Chd8+/N2373K mice with a human C-terminal-truncating mutation (N2373K) display autistic-like behaviors in juvenile and adult males but not in females. In contrast, Chd8+/S62X mice with a human N-terminal-truncating mutation (S62X) display behavioral deficits in juvenile males (not females) and adult males and females, indicative of age-differential sexually dimorphic behaviors. Excitatory synaptic transmission is suppressed and enhanced in male and female Chd8+/S62X juveniles, respectively, but similarly enhanced in adult male and female mutants. ASD-like transcriptomic changes are stronger in newborn and juvenile (but not adult) Chd8+/S62X males but in newborn and adult (not juvenile) Chd8+/S62X females. These results point to age-differential sexual dimorphisms in Chd8+/S62X mice at synaptic and transcriptomic levels, in addition to the behavioral level.

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“…3 C). Furthermore, ectoderm differentiation from hPSCs [ 25 , 26 ] in TFAM knockout group expressed much lower SOX1 (ectoderm) ( Fig. 3 D).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial dysfunction by TFAM depletion disrupts self-renewal and lineage differentiation of human PSCs by affecting cell proliferation and YAP response

Yan

Wang

et al. 2022

Redox Biology

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Genetic mitochondrial dysfunction is frequently associated with various embryonic developmental defects. However, how mitochondria contribute to early development and cell fate determination is poorly studied, especially in humans. Using human pluripotent stem cells (hPSCs), we established a Dox-induced knockout model with mitochondrial dysfunction and evaluated the effect of mitochondrial dysfunction on human pluripotency maintenance and lineage differentiation. The nucleus-encoded gene TFAM (transcription factor A, mitochondrial), essential for mitochondrial gene transcription and mitochondrial DNA replication, is targeted to construct the mitochondrial dysfunction model. The hPSCs with TFAM depletion exhibit the decrease of mtDNA level and oxidative respiration efficiency, representing a typical mitochondrial dysfunction phenotype. Mitochondrial dysfunction leads to impaired self-renewal in hPSCs due to proliferation arrest. Although the mitochondrial dysfunction does not affect pluripotent gene expression, it results in a severe defect in lineage differentiation. Further study in mesoderm differentiation reveals that mitochondrial dysfunction causes proliferation disability and YAP nuclear translocalization and thus together blocks mesoderm lineage differentiation. These findings provide new insights into understanding the mitochondrial function in human pluripotency maintenance and mesoderm differentiation.

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CHD8 safeguards early neuroectoderm differentiation in human ESCs and protects from apoptosis during neurogenesis

Cited by 9 publications

References 62 publications

PCGF6 controls neuroectoderm specification of human pluripotent stem cells by activating SOX2 expression

PCGF6 controls neuroectoderm specification of human pluripotent stem cells by activating SOX2 expression

Age-differential sexual dimorphisms in CHD8-S62X-mutant mouse synapses and transcriptomes

Mitochondrial dysfunction by TFAM depletion disrupts self-renewal and lineage differentiation of human PSCs by affecting cell proliferation and YAP response

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