Regulation of the microRNA processor DGCR8 by the tumor suppressor ING1
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PROVIDER: PRJNA121579 | ENA |
REPOSITORIES: ENA
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Project description:The ING familiy of tumor suppressor proteins control several cellular functions relevant to anti-tumor protection, like cell-cycle control, apoptosis, senescence or migration. ING proteins are functionally linked to the p53 pathway, and they participate in transcriptional control via the recognisition of histone marks and recruitment of protein complexes with chromatin-modifying activity to specific promoters. Here, we have investigated the global impact of ING1 in gene regulation through genome-wide analysis of expression profiles in primary embryonic fibroblasts deficient for the Ing1 locus. We find that Ing1 has a predominant role as transcriptional repressor in this setting, affecting the expression of genes involved in a variety of cellular functions. Within the subset of genes showing differential expression, we have identified DGCR8, a protein involved in the early steps of microRNA biogenesis. We show that ING1 binds to the DGCR8 promoter and controls its transcription through chromatin regulation at its promoter. We also find that ING1 and DGCR8 can cooperate in restraining proliferation. In summary, this study reveals a novel connection between ING1 and a regulator of microRNA biogenesis, and identifies new links between tumor suppressor proteins and the microRNA machinery For MEFs, two replicates were used for each genotype (wild-type or Ing1-deficient). Wild type MEFs were used as reference. For EMG cells [a cell line generated in our laboratory], two replicates were used for each condition (cells where ING1 was induced by doxycycline or uninduced cells). Uninduced cells were used as reference.
2010-06-20 | E-GEOD-18645 | biostudies-arrayexpress
Project description:The ING familiy of tumor suppressor proteins control several cellular functions relevant to anti-tumor protection, like cell-cycle control, apoptosis, senescence or migration. ING proteins are functionally linked to the p53 pathway, and they participate in transcriptional control via the recognisition of histone marks and recruitment of protein complexes with chromatin-modifying activity to specific promoters. Here, we have investigated the global impact of ING1 in gene regulation through genome-wide analysis of expression profiles in primary embryonic fibroblasts deficient for the Ing1 locus. We find that Ing1 has a predominant role as transcriptional repressor in this setting, affecting the expression of genes involved in a variety of cellular functions. Within the subset of genes showing differential expression, we have identified DGCR8, a protein involved in the early steps of microRNA biogenesis. We show that ING1 binds to the DGCR8 promoter and controls its transcription through chromatin regulation at its promoter. We also find that ING1 and DGCR8 can cooperate in restraining proliferation. In summary, this study reveals a novel connection between ING1 and a regulator of microRNA biogenesis, and identifies new links between tumor suppressor proteins and the microRNA machinery
2009-10-21 | GSE18645 | GEO
Project description:We investigated the effect of Dgcr8-homozygous mutation on microRNA expression profile in mouse embryonic stem cells. MicroRNA expression was substantially impaired, indicating a pivotal role of DGCR8 in microRNA biogenesis.
2010-09-01 | GSE20268 | 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:We investigated the effect of Dgcr8-homozygous mutation on microRNA expression profile in mouse embryonic stem cells. MicroRNA expression was substantially impaired, indicating a pivotal role of DGCR8 in microRNA biogenesis. MicroRNA expression profile was compared between Dgcr8-homozygous mutant ES cells and wild-type ES cells
2010-09-01 | E-GEOD-20268 | biostudies-arrayexpress
Project description:The ING familiy of tumor suppressor proteins control several cellular functions relevant to anti-tumor protection, like cell-cycle control, apoptosis, senescence or migration. ING proteins are functionally linked to the p53 pathway, and they participate in transcriptional control via the recognition of histone marks and recruitment of protein complexes with chromatin-modifying activity to specific promoters. Here, we have investigated the global impact of ING1 in gene regulation through genome-wide analysis of expression profiles in primary embryonic fibroblasts deficient for the Ing1 locus. We find that Ing1 has a predominant role as transcriptional repressor in this setting, affecting the expression of genes involved in a variety of cellular functions. Within the subset of genes showing differential expression, we have identified DGCR8, a protein involved in the early steps of microRNA biogenesis. In this study we have taken an unbiased approach to identify Ing1 targets, consisting in the comparison of expression profiles by genome-wide microarray analysis (Codelink mouse whole-genome expression microarrays), of mouse embryonic fibroblasts from embryos with the Ing1 locus inactivated by the insertion of a gene trap cassette, and their wild-type littermates. Three biological replicates were done for each phenotype.
2010-10-01 | E-GEOD-18519 | biostudies-arrayexpress
Project description:The DGCR8-UGU interaction in microRNA biogenesis
| PRJNA588809 | ENA
Project description:The ING familiy of tumor suppressor proteins control several cellular functions relevant to anti-tumor protection, like cell-cycle control, apoptosis, senescence or migration. ING proteins are functionally linked to the p53 pathway, and they participate in transcriptional control via the recognition of histone marks and recruitment of protein complexes with chromatin-modifying activity to specific promoters. Here, we have investigated the global impact of ING1 in gene regulation through genome-wide analysis of expression profiles in primary embryonic fibroblasts deficient for the Ing1 locus. We find that Ing1 has a predominant role as transcriptional repressor in this setting, affecting the expression of genes involved in a variety of cellular functions. Within the subset of genes showing differential expression, we have identified DGCR8, a protein involved in the early steps of microRNA biogenesis.
2010-10-01 | GSE18519 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE34679: Effects of Ars2 or DGCR8 siRNA on gene expression GSE34680: Effects of Ars2 or DGCR8 siRNA on microRNA expression Refer to individual Series
2012-02-01 | E-GEOD-34681 | biostudies-arrayexpress
Project description:Human Microprocessor is a trimeric complex composed of the RNase III enzyme, DROSHA, and a dimer of DGCR8 (its cofactor). Microprocessor initiates the biogenesis of microRNA by processing primary microRNAs (pri-miRNAs), during which, its cleavage efficiency and accuracy are enhanced because DGCR8 interacts with the apical UGU motif of pri-miRNAs. However, the mechanism of DGCR8-UGU interaction and influence of this interaction on the expression of cellular miRNA are still elusive. In this study, we demonstrated that the Rhed domain (i.e., the RNA-binding heme domain, amino acids 285-478) of DGCR8 is sufficient to recognize and interact with UGU. In addition, we identified three amino acid residues in Rhed (amino acids 361-363), which are critical for the UGU interaction, and we showed that these residues are essential for the Microprocessor complex to accurately and efficiently process pri-miRNAs in vitro. Furthermore, we found that within the DGCR8 dimer, the UGU-binding site from just one monomer is capable of discriminating between UGU- and non-UGU-containing pri-miRNAs. Finally, we showed that these amino acids are more important for the expression of UGU miRNAs than non-UGU miRNAs in human cells. This study improves our understanding of the substrate-recognizing mechanism of DGCR8, and implicates the roles of this recognition in differentiating miRNA expression in human cells.
2020-07-08 | GSE140209 | GEO