JMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells

Shan, Yongli; Zhang, Yanqi; Zhao, Yuan; Wang, Tianyu; Zhang, Jingyuan; Yao, Jiao; Ma, Ning; Liang, Zechuan; Huang, Wenhao; Huang, Ke; Zhang, Tian; Su, Zhenghui; Chen, Qianyu; Zhu, Yanling; Wu, Chuman; Zhou, Tiancheng; Sun, Wei; Wei, Yanxing; Zhang, Cong; Li, Chenxu; Su, Shuquan; Liao, Baojian; Zhong, Ming; Zhong, Xiaofen; Nie, Jinfu; Pei, Duanqing; Pan, Guoshun

doi:10.1038/s41467-019-14028-x

Cited by 52 publications

(43 citation statements)

References 66 publications

(74 reference statements)

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“…In the process of neurogenesis, we find that H3K27me3 levels were unchanged in the hESCs after the loss of UTX , and the differentiation potential of UTX KO hESCs to hNPCs is not affected. This finding supports the idea that maintaining the level of H3K27me3 may be important for the early stage of neurogenesis ( Shan et al., 2020 ).…”

Section: Discussionsupporting

confidence: 89%

UTX Regulates Human Neural Differentiation and Dendritic Morphology by Resolving Bivalent Promoters

et al. 2020

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Summary UTX , a H3K27me3 demethylase, plays an important role in mouse brain development. However, so little is known about the function of UTX in human neural differentiation and dendritic morphology. In this study, we generated UTX -null human embryonic stem cells using CRISPR/Cas9, and differentiated them into neural progenitor cells and neurons to investigate the effects of UTX loss of function on human neural development. The results showed that the number of differentiated neurons significantly reduced after loss of UTX , and that the dendritic morphology of UTX KO neurons tended to be simplified. The electrophysiological recordings showed that most of the UTX KO neurons were immature. Finally, RNA sequencing identified dozens of differentially expressed genes involved in neural differentiation and synaptic function in UTX KO neurons and our results demonstrated that UTX regulated these critical genes by resolving bivalent promoters. In summary, we establish a reference for the important role of UTX in human neural differentiation and dendritic morphology.

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Section: Discussionsupporting

confidence: 89%

UTX Regulates Human Neural Differentiation and Dendritic Morphology by Resolving Bivalent Promoters

et al. 2020

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“…The 53BP1-UTX interaction is required to upregulate key neurodevelopmental genes during the differentiation of human embryonic stem cells into neurons [37]. Yet another very recent investigation showed that knockout of UTX and/or JMJD3, encoding for another demethylase located on chromosome 17, determines the fidelity and lineage specification of human neural progenitor cells [38]. In their experiments they used hESC-H1, a male cell line, which means that the UTY gene is present.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Y-Encoded Demethylases During Differentiation of Human Male Neural Stem Cells

Pottmeier

Doszyn

Peuckert

et al. 2020

Stem Cells and Development

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Human neural stem cells (hNSCs) have long been used as an in vitro model to study neurogenesis and as candidates for nervous system therapy. Many parameters have been considered when evaluating the success of transplantation, but sex of donor and recipients is often not discussed. We investigated two commercial NSC lines, the female hNSC-H9 and male hNSC-H14, and we observed faster growth rates in the male cells. At 4 days of differentiation, male cells presented a significant increase in expression of DCX, an immature neuronal marker, while female cells showed a significant increase in RMST, a long noncoding RNA, which is indispensable during neurogenesis. In addition, expression of neural markers MAP2, PSD95, SYP, DCX, and TUJ1 at day 14 of differentiation suggested a similar differentiation potential in both lines. The most significant differences at day 14 of differentiation were the expression levels of RELN, with almost 100-fold difference between the sexes, and MASH1, with more than 1,000-fold increase in male cells. To evaluate whether some of the observed differences may be sex related, we measured the expression of gametologous genes located on the X-and Y-chromosome. Most noticeable was the increase of Y-encoded demethylases KDM6C (UTY) and KDM5D during differentiation of male cells. Our results indicate that attention should be paid to sex when planning neurogenesis and transplantation experiments.

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“…We hypothesized that Oct1 recruits H3K27-specific demethylases to lineage-specific bivalent genes to mediate their induction during differentiation. One such demethylase is Utx/Kdm6a (Cloos et al 2008), which has been shown to regulate neuronal differentiation (Shan et al 2020). In ChIP-qPCR experiments at the same Pax3 promoter, Utx was enriched at D6 of MD differentiation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Oct1 cooperates with Smad transcription factors to promote mesodermal lineage specification

Perovanović

Shen

et al. 2020

Preprint

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The pathways used to transition from an undifferentiated, pluripotent state into cell type-specific states are incompletely understood. Here we show that the transcription factor Oct1/Pou2f1 allows for correct induction of silent, developmental lineage-specific genes to canalize developmental progression. Using inducible-conditional Oct1 knockout embryonic stem cells and single-cell gene expression profiling, we show that mesodermal differentiation is impaired in the Oct1 deficient condition. Oct1 deficient cells fail to form late paraxial mesoderm and early somite stage populations, and show leaky developmental trajectories with inappropriate lineage branching and accumulation of poorly differentiated cells that retain gene expression and metabolic hallmarks of pluripotency. Oct1 directly binds and regulates genes critical for developmental regulation, including genes encoding mesoderm-specific master regulators and components of chromatin regulatory complexes. Oct1 positively resolves gene bivalency by recruiting Utx to mesoderm-specific, bivalent/poised targets, thereby removing inhibitory H3K27me3 chromatin marks to activate their expression. Oct1 deficient cells fail to remove H3K27me3 and positively resolve bivalency. Ectopic Oct1 expression improves the ability of cells to differentiate accurately under mesoderm lineage-inducing conditions.

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JMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells

Cited by 52 publications

References 66 publications

UTX Regulates Human Neural Differentiation and Dendritic Morphology by Resolving Bivalent Promoters

UTX Regulates Human Neural Differentiation and Dendritic Morphology by Resolving Bivalent Promoters

Increased Expression of Y-Encoded Demethylases During Differentiation of Human Male Neural Stem Cells

Oct1 cooperates with Smad transcription factors to promote mesodermal lineage specification

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