The DGCR8-UGU interaction in microRNA biogenesis
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ABSTRACT:
PROVIDER: PRJNA588809 | ENA |
REPOSITORIES: ENA
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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
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: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: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: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:Ars2 is a component of the nuclear cap-binding complex that is required for cellular proliferation and contributes to microRNA biogenesis. Arrays were performed to determine the repertoire of microRNAs that change following knock-down of Ars2. Knock-down of DGCR8 was also performed to determine which microRNAs were expressed and had half-lives short enough to significantly decrease over the duration of the experiment.
2012-02-01 | GSE34680 | GEO
Project description:Dgcr8 and Dicer are both important components of the microRNA biogenesis pathway while Dicer is also implicated in biogenesis of other types of small RNAs such as siRNAs and mirtrons. Here we performed microarray analysis of WT, Dgcr8 and Dicer knockout ES cells to identify mRNAs differentially regulated upon loss of Dgcr8 and Dicer.
2009-09-23 | GSE16923 | GEO
Project description:Ars2 is a component of the nuclear cap-binding complex that is required for cellular proliferation and contributes to microRNA biogenesis. Arrays were performed to determine the repertoire of microRNAs that change following knock-down of Ars2. Knock-down of DGCR8 was also performed to determine which microRNAs were expressed and had half-lives short enough to significantly decrease over the duration of the experiment. 9 samples were analyzed including: three biological replicates of control siRNA-transfected HeLa cells, HeLa cells transfected with three independent siRNAs targeting Ars2, or HeLa cells transfected with three independent siRNAs targeting DGCR8.
2012-02-01 | E-GEOD-34680 | 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 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: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