DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE209771 | GEO | 2025/02/14
REPOSITORIES: GEO
Similar Datasets
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
Project description:DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and attenuating aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its miRNA-processing activity, which is mediated by its C-terminal domains. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1 Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathologically and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA processing-independent role for DGCR8 in maintaining heterochromatin organization and attenuating senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
2019-05-28 | PXD013856 | Pride
Project description:DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and preventing aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its miRNA-processing activity, which is mediated by its C-terminal domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1gamma. Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
2018-04-14 | GSE113117 | GEO
Project description:To determine whether DGCR8 is required for maturation of all miRNAs, we performed miRNA microarray analysis. Using RNA from wild-type ES cells as our reference sample, we observed a global loss of miRNAs in DGCR8 knockout cells, but normal levels of expression in DGCR8 heterozygous cells. The similarity in expression levels between wild-type and heterozygous cells suggests that DGCR8 is not limiting in the maintenance of steady-state levels of miRNAs in ES cells. Of the eighty-nine miRNA array probes that showed significant signals with wild-type RNA, eighty-two were drastically reduced in the DGCR8 knockout cells. The remaining seven were not significantly altered in the DGCR8 knockout cells, but at least four of these seven miRNAs appear to be due to unavoidable contamination with RNA from the mouse embryonic fibroblast (MEF) feeder cells used for ES cell culture prior to the isolation of RNA. These miRNAs were highly expressed in the MEFs and decreased when the ES cells were temporarily passaged on gelatin-coated plates without feeders. The remaining three showed similar levels of expression in the heterozygous, knockout and MEF feeder cells. Therefore, these signals may be small RNAs that are not processed with the help of the microprocessor complex. Alternatively, these signals may result from unavoidable degradation products within the purified small RNA population. In either case, our results show that DGCR8 is broadly required for miRNA processing with little evidence for redundancy or bypass mechanisms. Keywords: cell type comparison, genetic modification MicroRNAs extracted from wild-type, DGCR8 heterozygous knockout and DGCR8 homozygous knockout were analyzed by microarray. In each array, wild-type samples serve as reference. Ratios were normalized based on positive control RNAs on the array. To determine if some of signals appeared in DGCR8 knockout ES cells are due to mice embryonic fibroblast (MEF) feeder cell contamination (this is unavoidable because these ES cells were grown on MEFs and passaged off MEF before RNA extraction). Two independent DGCR8 knockout ES cell lines were analyzed. For each cell line, array hybridization was done in duplicates. For DGCR8 heterozygous knockout ES cells, two independent batches of RNA samples were prepared and analyzed.
2010-06-11 | E-GEOD-6586 | biostudies-arrayexpress
Project description:DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and preventing aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its miRNA-processing activity, which is mediated by its C-terminal domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1g Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
2018-06-30 | GSE116303 | GEO
Project description:DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and preventing aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its miRNA-processing activity, which is mediated by its C-terminal domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1g expressing of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 expressing alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
2018-10-11 | GSE121029 | GEO
Project description:DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and preventing aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its miRNA-processing activity, which is mediated by its C-terminal domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1gamma Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
2018-04-17 | GSE113181 | GEO
Project description:DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and preventing aging. An N-terminal-truncated version of DGCR8 (DR8dex2) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its miRNA-processing activity, which is mediated by its C-terminal domain. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1g Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8dex2 hMSCs. Finally, DGCR8 was downregulated in pathological and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and osteoarthritis in mice. Taken together, these analyses uncovered a novel, miRNA-independent role for DGCR8 in maintaining heterochromatin organization and preventing senescence. DGCR8 may therefore represent a new therapeutic target for alleviating human aging-related disorders.
2019-04-24 | GSE130206 | GEO
Project description:To determine whether DGCR8 is required for maturation of all miRNAs, we performed miRNA microarray analysis. Using RNA from wild-type ES cells as our reference sample, we observed a global loss of miRNAs in DGCR8 knockout cells, but normal levels of expression in DGCR8 heterozygous cells. The similarity in expression levels between wild-type and heterozygous cells suggests that DGCR8 is not limiting in the maintenance of steady-state levels of miRNAs in ES cells. Of the eighty-nine miRNA array probes that showed significant signals with wild-type RNA, eighty-two were drastically reduced in the DGCR8 knockout cells. The remaining seven were not significantly altered in the DGCR8 knockout cells, but at least four of these seven miRNAs appear to be due to unavoidable contamination with RNA from the mouse embryonic fibroblast (MEF) feeder cells used for ES cell culture prior to the isolation of RNA. These miRNAs were highly expressed in the MEFs and decreased when the ES cells were temporarily passaged on gelatin-coated plates without feeders. The remaining three showed similar levels of expression in the heterozygous, knockout and MEF feeder cells. Therefore, these signals may be small RNAs that are not processed with the help of the microprocessor complex. Alternatively, these signals may result from unavoidable degradation products within the purified small RNA population. In either case, our results show that DGCR8 is broadly required for miRNA processing with little evidence for redundancy or bypass mechanisms. Keywords: cell type comparison, genetic modification
2007-01-31 | GSE6586 | GEO
Project description:Purpose: To compare the E9.5 Dgcr8 conditional knockout embryonic heart cells transfected with NC miRNA and miR-541 mimics Methods: In vitro cultured E9.5 Dgcr8 conditional KO heart cells transfected with miR-541-5p and NC miRNA were extracted with TRIZOL 48hrs after transfection, and 10ng total RNA was reverse transcribed and amplified by Smart-seq2 protocol as described (Picelli et al., 2014). Duplicated biological samples were analyzed using Illumina HiSeqX10, Clean reads were mapped to mouse genome (mm9) using BWA software. Results: Genes differentially expressed in E9.5 Dgcr8 cKO embryonic heart cells transfected with NC miRNA and miR-541 were identified. Conclusions: miRNA-541 significantly changes the gene expression profiles of E9.5 Dgcr8 cKO embryonic heart cells and promote the cardiac function
2018-09-12 | GSE96647 | GEO