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γH2A.X Modulates Self-renewal and Differentiation of Human Pluripotent Stem Cells. [HuGene-1_0-st]

ABSTRACT: Histone variants are important epigenetic regulators known to play a role in governing the processes of self-renewal and lineage specific differentiation . Phosphorylation of the histone variant H2A.X (γH2A.X) has historically been associated with DNA damage response, but more recent investigations have further demonstrated it’s role in cell cycle, aging and early development. Through both genetic and chemical targeting approaches, we now reveal a direct involvement of γH2A.X in hPSC self-renewal and differentiation decisions in vitro and in vivo. Namely, reduction of γH2A.X levels enhance hPSC differentiation toward mesodermal derivatives with concomitant inhibition of ectodermal derivatives. In contrast, ectopic expression of a constitutively phosphorylated mimic of γH2A.X enhanced hPSCs differentiation toward ectodermal fate while mesodermal differentiation was hindered. These phenotypic observations were associated with γH2A.X occupancy in the promoter regions of key regulatory genes associated with pluripotency and lineage choice. Our study suggests γH2A.X is a functional epigenetic pluripotency marker and novel target for guiding cell-fate commitment during differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE92643 | GEO | 2021/12/06

REPOSITORIES: GEO

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γH2A.X Modulates Self-renewal and Differentiation of Human Pluripotent Stem Cells. [HuGene-2_0-st]

Project description:Histone variants are important epigenetic regulators known to play a role in governing the processes of self-renewal and lineage specific differentiation . Phosphorylation of the histone variant H2A.X (γH2A.X) has historically been associated with DNA damage response, but more recent investigations have further demonstrated it’s role in cell cycle, aging and early development. Through both genetic and chemical targeting approaches, we now reveal a direct involvement of γH2A.X in hPSC self-renewal and differentiation decisions in vitro and in vivo. Namely, reduction of γH2A.X levels enhance hPSC differentiation toward mesodermal derivatives with concomitant inhibition of ectodermal derivatives. In contrast, ectopic expression of a constitutively phosphorylated mimic of γH2A.X enhanced hPSCs differentiation toward ectodermal fate while mesodermal differentiation was hindered. These phenotypic observations were associated with γH2A.X occupancy in the promoter regions of key regulatory genes associated with pluripotency and lineage choice. Our study suggests γH2A.X is a functional epigenetic pluripotency marker and novel target for guiding cell-fate commitment during differentiation.

2021-12-06 | GSE92642 | GEO

Phosphorylation state of the histone variant H2A.X controls human stem and progenitor cell fate decisions

Project description:Stem cell fate decisions are tightly regulated by several processes, including epigenetic based histone modifications. Histone variants (HVs) represent a subfamily of epigenetic regulators implicated in early embryonic development, but their role in stem cell fate control has not been targeted. Here we reveal direct involvement of phosphorylation state of the histone variant H2A.X that allows control of self-renewal and differentiation of human pluripotent stem cells (hPSCs) and leukemic patient derived progenitors. Reduced levels of γH2A.X using either genetic approaches or chemical targeting allowed enhanced hPSC differentiation toward the mesodermal (hematopoietic) lineage with concomitant inhibition of ectodermal (neural) development. In contrast, activation and sustained levels of phosphorylated H2A.X enhanced hPSC ectodermal fate while suppressing mesodermal derived hematopoiesis. This controlled bifurcation of neural vs. hematopoietic differentiation correlated to occupancy of γH2A.X at gene loci associated with lineage selection. Drug modulation of H2A.X phosphorylation was extended to somatic cells to reveal the ability to induce differentiation of leukemic progenitors and serve as a biomarker in a cohort of adult leukemic patients. Our study uncovers a mechanism of cell-fate control of hPSCs extended to neoplastic progenitors through a histone variant epigenetic regulation

2021-03-09 | GSE164680 | GEO

RNA-seq analysis of substates of human pluripotent stem cells with mesoderm bias and early differentiating cells towards the mesoderm lineage

Project description:The differentiation of human pluripotent stem cells (hPSC) towards clinically relevant cells for regenerative medicine has been hampered by poor differentiation efficiencies. This may be a result, in part, of the heterogeneity that exists within stem cell cultures. We have generated a new stem cell medium PRIMO, which biases cells towards mesodermal differentiation without losing pluripotency. This experiment characterizes the gene expression of cells grown in PRIMO and compares this to cells grown in standard culture conditions and a 72 hour time course of mesodermal differentiation

2020-08-31 | E-MTAB-9474 | biostudies-arrayexpress

Maintenance of pluripotency signature in the entire ectoderm enables potential for neural crest formation

Project description:The ability of the pluripotent epiblast to contribute progeny to all three germ layers is thought to be lost after gastrulation. The later-forming neural crest (NC) rises from ectoderm and it remains poorly understood how its exceptionally high stem-cell potential to generate mesodermal- and endodermal-like cells is obtained. We monitored transcriptional changes from gastrulation to neurulation using single-cell-Multiplex-Spatial-Transcriptomics (scMST) complemented with RNA-sequencing. Unexpectedly, we find maintenance of undecided Nanog/Oct4-PouV/Klf4-positive pluripotent-like pan-ectodermal stem-cells spanning the entire ectoderm late in the neurulation process with ectodermal patterning completed only at the end of neurulation when pluripotency becomes restricted to NC, challenging our understanding of gastrulation. Furthermore, broad ectodermal pluripotency is found at all axial levels unrelated to the NC lineage the cells later commit to, suggesting a general role in stemness enhancement and proposing a mechanism by which the NC acquires its ability to form derivatives beyond “ectodermal-capacity” in chick and mouse embryos.

2023-08-28 | GSE232432 | GEO

Maintenance of pluripotency signature in the entire ectoderm enables potential for neural crest formation [scRNASeq]

Project description:The ability of the pluripotent epiblast to contribute progeny to all three germ layers is thought to be lost after gastrulation. The later-forming neural crest (NC) rises from ectoderm and it remains poorly understood how its exceptionally high stem-cell potential to generate mesodermal- and endodermal-like cells is obtained. We monitored transcriptional changes from gastrulation to neurulation using single-cell-Multiplex-Spatial-Transcriptomics (scMST) complemented with RNA-sequencing. Here we show maintenance of pluripotency-signature (Nanog/Oct4-PouV/Klf4-positive) in undecided pan-ectodermal stem-cells spanning the entire ectoderm late during neurulation with ectodermal patterning completed only at the end of neurulation when the pluripotency-signature becomes restricted to NC, challenging our understanding of gastrulation. Furthermore, broad ectodermal pluripotency-signature is found at all axial levels unrelated to the NC lineage the cells later commit to, suggesting a general role in stemness enhancement and proposing a mechanism by which the NC acquires its ability to form derivatives beyond “ectodermal-capacity” in chick and mouse embryos.

2023-03-02 | GSE221188 | GEO

Maintenance of pluripotency signature in the entire ectoderm enables potential for neural crest formation [bulk_RNASeq]

Project description:The ability of the pluripotent epiblast to contribute progeny to all three germ layers is thought to be lost after gastrulation. The later-forming neural crest (NC) rises from ectoderm and it remains poorly understood how its exceptionally high stem-cell potential to generate mesodermal- and endodermal-like cells is obtained. We monitored transcriptional changes from gastrulation to neurulation using single-cell-Multiplex-Spatial-Transcriptomics (scMST) complemented with RNA-sequencing. Here we show maintenance of pluripotency-signature (Nanog/Oct4-PouV/Klf4-positive) in undecided pan-ectodermal stem-cells spanning the entire ectoderm late during neurulation with ectodermal patterning completed only at the end of neurulation when the pluripotency-signature becomes restricted to NC, challenging our understanding of gastrulation. Furthermore, broad ectodermal pluripotency-signature is found at all axial levels unrelated to the NC lineage the cells later commit to, suggesting a general role in stemness enhancement and proposing a mechanism by which the NC acquires its ability to form derivatives beyond “ectodermal-capacity” in chick and mouse embryos.

2023-03-02 | GSE221125 | GEO

Alternative Splicing of MBD2 Supports Self-Renewal in Human Pluripotent Stem Cells [HJAY]

Project description:Alternative RNA splicing (AS) regulates proteome diversity, including isoform-specific expression of several pluripotency genes. Here, we integrated global gene expression and proteomic analyses and identified a molecular signature suggesting a central role for AS in maintaining human pluripotent stem cell (hPSC) self-renewal. We demonstrate the splicing factor SFRS2 is an OCT4 target gene required for pluripotency. SFRS2 regulates AS of the methyl-CpG-binding protein MBD2, whose isoforms play opposing roles in maintenance of, and reprogramming to, pluripotency. While both MDB2a and MBD2c are enriched at the OCT4 and NANOG promoters, MBD2a preferentially interacts with repressive NuRD chromatin remodeling factors and promotes hPSC differentiation, whereas overexpression of MBD2c enhances reprogramming of fibroblasts to pluripotency. The miR-301 and miR-302 families provide additional regulation by targeting SFRS2 and MDB2a. These data suggest that OCT4, SFRS2, and MBD2 participate in a positive feedback loop, regulating proteome diversity complexity in support of hPSC self-renewal and reprogramming. We isolated RNA from human fibroblasts and human embryonic stem cells for hybridization to the Affymetrix gene expression microarrays.

2014-04-20 | E-GEOD-55678 | biostudies-arrayexpress

CTCF deletion alters the pluripotency and DNA methylation profile of human iPSCs (methylation)

Project description:Pluripotent stem cells are characterized by their differentiation potential toward endoderm, mesoderm, and ectoderm. However, it is still largely unclear how these cell-fate decisions are mediated by epigenetic mechanisms. In this study, we explored the relevance of CCCTC-binding factor (CTCF), a zinc finger-containing DNA-binding protein, which mediates long-range chromatin organization, for directed cell-fate determination. We generated human induced pluripotent stem cell (iPSC) lines with deletions in the protein-coding region in exon 3 of CTCF, resulting in overall reduced expression and shorter transcripts. These lines showed a considerable loss of CTCF binding to target sites. The CTCF deletions resulted in slower growth and modest global changes in gene expression, with down-regulation of a subset of pluripotency-associated genes and neuroectodermal genes. CTCF deletion also evoked DNA methylation changes, which were moderately associated with differential gene expression. Notably, CTCF-deletions lead to up-regulation of endo-mesodermal associated marker genes and epigenetic signatures, whereas ectodermal differentiation was defective. These results indicate that CTCF plays an important role in the maintenance of pluripotency and differentiation, especially towards ectodermal lineages.

2023-11-24 | GSE247427 | GEO

CTCF deletion alters the pluripotency and DNA methylation profile of human iPSCs (RNA-Seq)

2023-11-24 | GSE247426 | GEO

In vitro cultured H7 human embryonic stem cells (WiCell) and H7-derived downstream early mesoderm progenitors

Project description:Stem-cell differentiation to desired lineages requires navigating alternating developmental paths that often lead to unwanted cell types. Hence, comprehensive developmental roadmaps are crucial to channel stem-cell differentiation toward desired fates. To this end, here, we map bifurcating lineage choices leading from pluripotency to 12 human mesodermal lineages, including bone, muscle, and heart. We defined the extrinsic signals controlling each binary lineage decision, enabling us to logically block differentiation toward unwanted fates and rapidly steer pluripotent stem cells toward 80%â99% pure human mesodermal lineages at most branchpoints. This strategy enabled the generation of human bone and heart progenitors that could engraft in respective in vivo models. Mapping stepwise chromatin and single-cell gene expression changes in mesoderm development uncovered somite segmentation, a previously unobservable human embryonic event transiently marked by HOPX expression. Collectively, this roadmap enables navigation of mesodermal development to produce transplantable human tissue progenitors and uncover developmental processes. doi:10.1016/j.cell.2016.06.011 BioProject: PRJNA319573, Study: SRP073808, Bulk and single-cell RNA-seq, and ATAC-seq of of H7 human embryonic stem cells (ESC) and in vitro derived 10 diffrerent mesoderm progenitors from H7-ESC

2016-08-02 | E-GEOD-85066 | biostudies-arrayexpress

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