Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

MicroRNA expression in bone marrow cells from Gfi1 deficient mice

ABSTRACT: Growth factor independent-1 (Gfi1) is a zinc finger transcription factor with a SNAG amino-terminal repressor domain and is critically required for normal myelopoesis. Gfi1 is normally expressed in HSCs and induced during differentiation from CMPs to GMPs. Gfi1 loss-of-function mutation in mice and humans induces an arrest during myeloid differentiation and an absolute block to the formation mature neutrophils. This comparative microarray study was initiated to identify microRNAs which are potentially regulated by Gfi1 during granulopoiesis. The Gfi1 null allele from Orkin (deletion of exons 2 and 3) was backcrossed to B6 or Balb/c mice for at least 7 generations. RNA was isolated from low density bone marrow samples from Gfi1+/+ and Gfi1-/- B6 littermates, as well as Gfi1+/+ and Gfi1-/- Balb/c littermates.

ORGANISM(S): Mus musculus

SUBMITTER: Terry Camerlengo

PROVIDER: E-GEOD-15077 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Gfi1 regulates miR-21 and miR-196b to control myelopoiesis.

Velu Chinavenmeni S CS Baktula Avinash M AM Grimes H Leighton HL

Blood 20090310 19

The zinc finger protein growth factor independent-1 (Gfi1) is a transcriptional repressor that is critically required for normal granulocytic differentiation. GFI1 loss-of-function mutations are found in some patients with severe congenital neutropenia (SCN). The SCN-associated GFI1-mutant proteins act as dominant negatives to block granulopoiesis through selective deregulation of a subset of GFI1 target genes. Here we show that Gfi1 is a master regulator of microRNAs, and that deregulated expre ...[more]

PMID: 19278956

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Project description:GFI1 is a transcriptional repressor protein that plays an essential role in HSCs development, lymphoid and myeloid differentiation and Acute Myeloid Leukaemic (AML) pathogenesis. Low expression levels of GFI1 is associated with a poor prognosis in AML development. In addition, a single nucleotide polymorphism (SNP) variant of GFI1 results in the generation of GFI1 protein with asparagine (N) instead of serine (S) at the 36th amino acid position, known as GFI136N. Expression of the GFI1-36N allele leads as well to poor prognosis and promotes AML development. In this study, we demonstrated with the help of RNAseq transcriptomic analysis that the presence of GFI1-36N is associated with increased frequency of chromosomal aberrations and mutational burden in murine and human AML cells. In particular, GFI1-36N modulates DNA repair pathways, O6-methylguanine-DNA-methyltransferase (MGMT)-mediated repair and homologous recombination repair (HR). Mechanistically, GFI1-36N exhibits impaired binding to Ndrg1 promoter element compared to GFI1-36S (wild type), causing decreased NDRG1 levels, consequently leading to suppression of MGMT expression, imprinted at the transcriptome and proteome, thus leaving the AML cells vulnerable to DNA damaging agents. Furthermore, we showed that a low expression level of GFI1 in leukemic cells is associated with high OXPHOS and enhanced glutamine metabolism. However, we hypothesise that the observed metabolic phenotype is mediated through FOXO1 protein. RNAseq transcriptomic analysis revealed higher Foxo1 mRNA expression levels with lower GFI1 expression, providing the first hint of Foxo1 as a potential target gene of GFI1 protein. The mRNA and protein levels of high Foxo1 with reduced GFI1 expression was confirmed by RT-PCR and western blot, respectively. In addition, CHIPseq and ATACseq analysis further proved that Foxo1 is a potential target gene of GFI1. In summary, we show that GFI1 plays a role during DNA repair and metabolism and thus provides critical insights into a novel therapeutic option for AML patients carrying the GFI1-36N variant or having a low expression level of GFI1.

Dataset Information

MicroRNA expression in bone marrow cells from Gfi1 deficient mice

Publications

Gfi1 regulates miR-21 and miR-196b to control myelopoiesis.

Similar Datasets

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