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Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and Reprogramming Defects [RNA-seq]

ABSTRACT: Transcription profile analysis at day 6 of reprogramming to iPSCs revealed dissimilarities between NGFP2 N+/- and the double heterozygous mutant lines : NGFP2 N+/-;S+/-, NGFP2 N+/-;E+/-, NGFP2 N+/-;U+/-

ORGANISM(S): Mus musculus

PROVIDER: GSE192652 | GEO | 2023/11/27

REPOSITORIES: GEO

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Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and Reprogramming Defects

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-11-27 | GSE192655 | GEO

Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and Reprogramming Defects

Project description:Gene expression comparison between various pluripotent stem cell lines (as indicated below) that grew under 2i/Lif or S/Lif conditions

2022-06-16 | GSE182009 | GEO

Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and Reprogramming Defects [BiSulfite-seq]

Project description:SGFP1 S2+/- and SGFP1 S2+/-;S4+/- MEFs show different methylation profiles and expose methylated genes specific to the SGFP1 S2+/-;S4+/- MEFs that are important for reprograming

2023-11-27 | GSE192481 | GEO

Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and Reprogramming Defects

Project description:Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and Reprogramming Defects

| PRJNA754173 | ENA

Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and Reprogramming Defects

Project description:Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and Reprogramming Defects

| PRJNA792565 | ENA

Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and Reprogramming Defects [BiSulfite-seq]

Project description:Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and Reprogramming Defects [BiSulfite-seq]

| PRJNA791640 | ENA

Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and Reprogramming Defects [RNA-seq]

| PRJNA792559 | ENA

Complex haploinsufficiency in pluripotent cells yields somatic cells with DNA methylation abnormalities and pluripotency induction defects.

Project description:A complete knockout of a single key pluripotency gene may drastically affect embryonic stem cell function and epigenetic reprogramming. In contrast, elimination of only one allele of a single pluripotency gene is mostly considered harmless to the cell. To understand whether complex haploinsufficiency exists in pluripotent cells, we simultaneously eliminated a single allele in different combinations of two pluripotency genes (i.e., Nanog+/-;Sall4+/-, Nanog+/-;Utf1+/-, Nanog+/-;Esrrb+/- and Sox2+/-;Sall4+/-). Although these double heterozygous mutant lines similarly contribute to chimeras, fibroblasts derived from these systems show a significant decrease in their ability to induce pluripotency. Tracing the stochastic expression of Sall4 and Nanog at early phases of reprogramming could not explain the seen delay or blockage. Further exploration identifies abnormal methylation around pluripotent and developmental genes in the double heterozygous mutant fibroblasts, which could be rescued by hypomethylating agent or high OSKM levels. This study emphasizes the importance of maintaining two intact alleles for pluripotency induction.

| S-EPMC10679652 | biostudies-literature

Mice carrying a hypomorphic Evi1 allele are embryonic viable but exhibit severe congenital heart defects.

Project description:The ecotropic viral integration site 1 (Evi1) oncogenic transcription factor is one of a number of alternative transcripts encoded by the Mds1 and Evi1 complex locus (Mecom). Overexpression of Evi1 has been observed in a number of myeloid disorders and is associated with poor patient survival. It is also amplified and/or overexpressed in many epithelial cancers including nasopharyngeal carcinoma, ovarian carcinoma, ependymomas, and lung and colorectal cancers. Two murine knockout models have also demonstrated Evi1's critical role in the maintenance of hematopoietic stem cell renewal with its absence resulting in the death of mutant embryos due to hematopoietic failure. Here we characterize a novel mouse model (designated Evi1(fl3)) in which Evi1 exon 3, which carries the ATG start, is flanked by loxP sites. Unexpectedly, we found that germline deletion of exon3 produces a hypomorphic allele due to the use of an alternative ATG start site located in exon 4, resulting in a minor Evi1 N-terminal truncation and a block in expression of the Mds1-Evi1 fusion transcript. Evi1(δex3/δex3) mutant embryos showed only a mild non-lethal hematopoietic phenotype and bone marrow failure was only observed in adult Vav-iCre/+, Evi1(fl3/fl3) mice in which exon 3 was specifically deleted in the hematopoietic system. Evi1(δex3/δex3) knockout pups are born in normal numbers but die during the perinatal period from congenital heart defects. Database searches identified 143 genes with similar mutant heart phenotypes as those observed in Evi1(δex3/δex3) mutant pups. Interestingly, 42 of these congenital heart defect genes contain known Evi1-binding sites, and expression of 18 of these genes are also effected by Evi1 siRNA knockdown. These results show a potential functional involvement of Evi1 target genes in heart development and indicate that Evi1 is part of a transcriptional program that regulates cardiac development in addition to the development of blood.

| S-EPMC3937339 | biostudies-literature

Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects

Project description:Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease of the hematopoietic system, which is caused by heterozygous mutations in RUNX1. FPD/AML patients have a bleeding disorder characterized by thrombocytopenia with reduced platelet numbers and functions, and a tendency to develop AML. Currently no suitable animal models exist for FPD/AML as Runx1+/- mice and zebrafish do not develop bleeding disorders or leukemia. Here we derived induced pluripotent stem cells (iPSCs) from two patients in a family with FPD/AML, and found that the FPD iPSCs display defects in megakaryocytic differentiation in vitro. We corrected the RUNX1 mutation in one FPD iPSC line through gene targeting, which led to normalization of megakaryopoiesis of the iPSCs in culture. Our results demonstrate successful in vitro modeling of FPD with patient-specific iPSCs and confirm that RUNX1 mutations are responsible for megakaryopoietic defects in FPD patients. Here, we derived iPSCs from two FPD/AML patients and demonstrated that these iPSCs have a megakaryopoietic defect in culture. Importantly we were able to rescue the megakaryopoietic defect by correcting the RUNX1 mutation with a gene targeting strategy enhanced by zinc finger nucleases (ZFNs). Three independent samples were obtained for each time point.

2014-07-01 | E-GEOD-54295 | biostudies-arrayexpress

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