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UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE108116 | GEO | 2019/02/15

REPOSITORIES: GEO

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UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells [RNA-seq]

Project description:UTX is a histone H3 lysine 27 demethylase required for development. However, the mechanisms underlying developmental gene regulation by UTX are unclear. Here, we discovered a molecular interaction between UTX and 53BP1 that regulates gene expression in a human neurogenesis model. Human 53BP1 contains a UTX-binding site that diverges from its mouse homolog by 41%, and our data suggest that the UTX-53BP1 interaction is conserved in primates but not rodents. ChIP-Seq revealed that the genome-wide targets of UTX and 53BP1 overlap by 84%. We used CRISPR-Cas9 to generate mutations of 53BP1 and UTX in human embryonic stem cells, and found that both 53BP1 and UTX are required to promote the expression of hundreds of neurogenic genes during neural differentiation. Further, 53BP1 is required for human neural progenitor differentiation into neurons. Our findings suggest that the UTX-53BP1 interaction controls gene expression important for neural differentiation in humans.

2019-02-15 | GSE108115 | GEO

UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells [ChIP-seq]

2019-02-15 | GSE108114 | GEO

UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells [mouse RNA-seq]

2019-02-15 | GSE120333 | GEO

UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells

Project description:UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells

| PRJNA422467 | ENA

UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells [RNA-seq]

Project description:UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells [RNA-seq]

| PRJNA422469 | ENA

UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells [ChIP-seq]

Project description:UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells [ChIP-seq]

| PRJNA422470 | ENA

UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells [mouse RNA-seq]

Project description:UTX and 53BP1 co-regulate genetic programs for neural differentiation of human embryonic stem cells [mouse RNA-seq]

| PRJNA492495 | ENA

Differentiation of human pluripotent stem cells into neurons or cortical organoids requires transcriptional co-regulation by UTX and 53BP1.

Project description:UTX is a chromatin modifier required for development and neural lineage specification, but how it controls these biological processes is unclear. To determine the molecular mechanisms of UTX, we identified novel UTX protein interaction partners. Here we show that UTX and 53BP1 directly interact and co-occupy promoters in human embryonic stem cells and differentiating neural progenitor cells. Human 53BP1 contains a UTX-binding site that diverges from its mouse homolog by 41%, and disruption of the 53BP1-UTX interaction abrogated human, but not mouse, neurogenesis in vitro. The 53BP1-UTX interaction is required to upregulate key neurodevelopmental genes during the differentiation of human embryonic stem cells into neurons or into cortical organoids. 53BP1 promotes UTX chromatin binding, and in turn H3K27 modifications and gene activation, at a subset of genomic regions, including neurogenic genes. Overall, our data suggest that the 53BP1-UTX interaction supports the activation of key genes required for human neurodevelopment.

| S-EPMC6511450 | biostudies-literature

UTX Affects Neural Stem Cell Proliferation and Differentiation through PTEN Signaling.

Project description:Neural stem cell (NSC) proliferation and differentiation in the developing brain is a complex process precisely regulated by intrinsic and extrinsic signals. Although epigenetic modification has been reportedly involved in the regulation of the cerebral cortex, whether UTX, an H3K27me3 demethylase, regulates the development of cerebral cortex during the embryonic period is unclear. In this study, we demonstrate that Utx deficiency by knockdown and conditional knockout increases NSC proliferation and decreases terminal mitosis and neuronal differentiation. Furthermore, we find that impairment of cortical development caused by lack of Utx is less significant in males than in females. In addition, UTX demethylates H3K27me3 at the Pten promoter and promotes Pten expression. P-AKT and P-mTOR levels are increased in the Utx conditional knockout cortices. Finally, Utx or Pten overexpression can rescue the impairment of brain development caused by Utx loss. These findings may provide important clues toward deciphering brain diseases.

| S-EPMC5998300 | biostudies-literature

UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity.

Project description:To investigate the role of histone H3K27 demethylase UTX in embryonic stem (ES) cell differentiation, we have generated UTX knockout (KO) and enzyme-dead knock-in male ES cells. Deletion of the X-chromosome-encoded UTX gene in male ES cells markedly decreases expression of the paralogous UTY gene encoded by Y chromosome, but has no effect on global H3K27me3 level, Hox gene expression, or ES cell self-renewal. However, UTX KO cells show severe defects in mesoderm differentiation and induction of Brachyury, a transcription factor essential for mesoderm development. Surprisingly, UTX regulates mesoderm differentiation and Brachyury expression independent of its enzymatic activity. UTY, which lacks detectable demethylase activity, compensates for the loss of UTX in regulating Brachyury expression. UTX and UTY bind directly to Brachyury promoter and are required for Wnt/β-catenin signaling-induced Brachyury expression in ES cells. Interestingly, male UTX KO embryos express normal levels of UTY and survive until birth. In contrast, female UTX KO mice, which lack the UTY gene, show embryonic lethality before embryonic day 11.5. Female UTX KO embryos show severe defects in both Brachyury expression and embryonic development of mesoderm-derived posterior notochord, cardiac, and hematopoietic tissues. These results indicate that UTX controls mesoderm differentiation and Brachyury expression independent of H3K27 demethylase activity, and suggest that UTX and UTY are functionally redundant in ES cell differentiation and early embryonic development.

| S-EPMC3458330 | biostudies-literature

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