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DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE209843 | GEO | 2025/02/14

REPOSITORIES: GEO

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DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects

Project description:The 22q11.2 deletion syndrome (22qDS) is caused by a microdeletion in one of the chromosomes 22, comprising around 40 genes and including DGCR8, an essential gene for miRNA biogenesis and transposable elements control. Most of the clinical manifestations of 22qDS have their origin during embryonic development, but the contribution of human DGCR8 hemizygosity to the disease is unknown. To clarify the overall effect of DGCR8 in the context of 22qDS, we have generated two human embryonic models of DGCR8 +/-.In this dataset we use small RNA-seq to study the effect of DGCR8 heterozygosity on steady state miRNA levels in human embryonic stem cells.

2025-02-14 | GSE209771 | GEO

DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects

Project description:The 22q11.2 deletion syndrome (22qDS) is caused by a microdeletion in one of the chromosomes 22, comprising around 40 genes and including DGCR8, an essential gene for miRNA biogenesis and transposable elements control. Most of the clinical manifestations of 22qDS have their origin during embryonic development, but the contribution of human DGCR8 hemizygosity to the disease is unknown. To clarify the overall effect of DGCR8 in the context of 22qDS, we have generated two human embryonic models of DGCR8 +/-.In this dataset we use total RNA-seq to study the effect of DGCR8 heterozygosity on steady state RNA levels in human embryonic stem cells.

2025-02-14 | GSE209770 | GEO

DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects

Project description:DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects

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DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects

Project description:DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects

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DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects

Project description:DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects

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Senescence leads to epigenomic disruption invoking hallmarks of reprogramming and pluripotency

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-12-15 | E-GEOD-53332 | biostudies-arrayexpress

Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential.

Project description:Claspin is an adaptor protein required for ATR-dependent phosphorylation of CHK1 during S-phase following DNA replication stress. Claspin expression is highly variable in cancer, with low levels frequently correlating with poor patient survival. To learn more about the biological consequences of reduced Claspin expression and its effects on tumorigenesis, we investigated mice with a heterozygous knockout of the Clspn gene. Claspin haploinsufficiency resulted in reduced female fertility and a maternally inherited defect in oocyte meiosis I cell cycle progression. Furthermore, aged Clspn+/- mice developed spontaneous lymphoid hyperplasia and increased susceptibility to non-alcoholic fatty liver disease. Importantly, we demonstrate a tumour suppressor role for Claspin. Reduced Claspin levels result in increased liver damage and tumourigenesis in the DEN model of hepatocellular carcinoma. These data reveal that Clspn haploinsufficiency has widespread unanticipated biological effects and establishes the importance of Claspin as a regulatory node controlling tumorigenesis and multiple disease aetiologies.

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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.

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Noncanonical function of DGCR8 controls mESC exit from pluripotency.

Project description:Mouse embryonic stem cells (mESCs) deficient for DGCR8, a key component of the microprocessor complex, present strong differentiation defects. However, the exact reasons impairing their commitment remain elusive. The analysis of newly generated mutant mESCs revealed that DGCR8 is essential for the exit from the pluripotency state. To dissociate canonical versus noncanonical functions of DGCR8, we complemented the mutant mESCs with a phosphomutant DGCR8, which restored microRNA levels but did not rescue the exit from pluripotency defect. Integration of omics data and RNA immunoprecipitation experiments established DGCR8 as a direct interactor of Tcf7l1 mRNA, a core component of the pluripotency network. Finally, we found that DGCR8 facilitated the splicing of Tcf7l1, an event necessary for the differentiation of mESCs. Our data reveal a new noncanonical function of DGCR8 in the modulation of the alternative splicing of Tcf7l1 mRNA in addition to its established function in microRNA biogenesis.

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Dysregulation of NIPBL leads to impaired RUNX1 expression and haematopoietic defects.

Project description:The transcription factor RUNX1, a pivotal regulator of HSCs and haematopoiesis, is a frequent target of chromosomal translocations, point mutations or altered gene/protein dosage. These modifications lead or contribute to the development of myelodysplasia, leukaemia or platelet disorders. A better understanding of how regulatory elements contribute to fine-tune the RUNX1 expression in haematopoietic tissues could improve our knowledge of the mechanisms responsible for normal haematopoiesis and malignancy insurgence. The cohesin RAD21 was reported to be a regulator of RUNX1 expression in the human myeloid HL60 cell line and during primitive haematopoiesis in zebrafish. In our study, we demonstrate that another cohesin, NIPBL, exerts positive regulation of RUNX1 in three different contexts in which RUNX1 displays important functions: in megakaryocytes derived from healthy donors, in bone marrow samples obtained from adult patients with acute myeloid leukaemia and during zebrafish haematopoiesis. In this model, we demonstrate that alterations in the zebrafish orthologue nipblb reduce runx1 expression with consequent defects in its erythroid and myeloid targets such as gata1a and spi1b in an opposite way to rad21. Thus, also in the absence of RUNX1 translocation or mutations, additional factors such as defects in the expression of NIPBL might induce haematological diseases.

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