Effect of Gfi1 36N variant on genome-wide H3K9 Acetylation patterns
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE71254 | GEO | 2016/08/01
SECONDARY ACCESSION(S): PRJNA290712
REPOSITORIES: GEO
Similar Datasets
Project description:ChIP-Seq Analysis of H3K9Ac in pairs of mouse and human samples carrying either the Gfi136S or the GFi136N variants. The objective of the study was to identify the changes in H3K9 acetylation at gene promoters that occur in samples expressing the 36N variant of the Gfi1 gene. 3 pairs of bone-marrow AML samples were obtained from mice where 1 mouse in each pair was homozygous for Gfi136S and 1 heterozygous for Gfi136N, or homozygous for 36N in one case. 2 pairs of AML samples were obtained from human patients were 1 patient was homozygous for Gfi1 36S and one was heterozygous for Gfi1 36N. H3 and H3K9Ac ChIP-Seq was carried out on each sample.
2016-08-01 | E-GEOD-71254 | biostudies-arrayexpress
Project description:Effect of Gfi1 36N variant on genome-wide H3K9 Acetylation patterns
| PRJNA290712 | ENA
Project description:GFI136N is a coding Single Nucleotide Polymorphism (SNP) in the gene GFI1 that increases the risk for Acute myeloid leukemia (AML) by 60%. It is present in 3-5% of Caucasians and has a prevalence of 12% among AML patients. We generated knockin mice expressing either the human GFI136N variant or the more common GFI136S form and observed that GFI136N, in contrast to GFI136S, lacked the ability to bind to the Gfi1 target gene and leukemia associated transcription factor Hoxa9 in myeloid precursors and failed to initiate the histone modifications that regulate HoxA9 expression. Consistent with this, GFI136N heterozygous AML patients showed increased HOXA9 expression compared to control patients. In the knockin mice, granulo-monocytic pogenitors (GMPs), a bone marrow subset from which AML can arise, show a proliferative expansion in the presence of the GFI136N variant. Finally, the GFI136N variant increased colony formation and proliferation of myeloid precursors induced by the onco-fusion proteins MLL/AF9 or AML1/Eto9a and accelerated the onset of a KRAS-driven myelo-proliferative disease. Our data suggest that GFI136N predisposes to AML by deregulating the expression of Hoxa9, a locus highly relevant for AML, thereby inducing a pre-leukemic state in myeloid precursors that can give rise to AML. 3 samples (2 histone modifications, 1 transcription factor)
2012-12-04 | E-GEOD-31657 | biostudies-arrayexpress
Project description:GFI136N is a coding Single Nucleotide Polymorphism (SNP) in the gene GFI1 that increases the risk for Acute myeloid leukemia (AML) by 60%. It is present in 3-5% of Caucasians and has a prevalence of 12% among AML patients. We generated knockin mice expressing either the human GFI136N variant or the more common GFI136S form and observed that GFI136N, in contrast to GFI136S, lacked the ability to bind to the Gfi1 target gene and leukemia associated transcription factor Hoxa9 in myeloid precursors and failed to initiate the histone modifications that regulate HoxA9 expression. Consistent with this, GFI136N heterozygous AML patients showed increased HOXA9 expression compared to control patients. In the knockin mice, granulo-monocytic pogenitors (GMPs), a bone marrow subset from which AML can arise, show a proliferative expansion in the presence of the GFI136N variant. Finally, the GFI136N variant increased colony formation and proliferation of myeloid precursors induced by the onco-fusion proteins MLL/AF9 or AML1/Eto9a and accelerated the onset of a KRAS-driven myelo-proliferative disease. Our data suggest that GFI136N predisposes to AML by deregulating the expression of Hoxa9, a locus highly relevant for AML, thereby inducing a pre-leukemic state in myeloid precursors that can give rise to AML.
2012-12-04 | GSE31657 | GEO
Project description:The incidence of cancer is not only influenced by exposure to environmental factors such as toxic substances and chemotherapy, but is also a result of individual predispositions. Single Nucleotide Polymorphisms (SNPs) represent one such individual predisposition to cancer1. Gfi136N is a SNP in the coding region of the gene “Growth factor independence 1 (Gfi1)” predisposing to development of Acute myeloid leukemia (AML). However, the mechanisms how this polymorphism is associated with AML are unknown. Here we present a mouse model in which the presence of Gfi136N leads to altered epigenetic modifications in the myeloid progenitor fraction “Granulocytic Monocytic Progenitor (GMP)” and demonstrates how this might predispose to AML. Presence of Gfi136N leads to a different epigenetic programming of the GMPs resulting in higher levels of the leukemogenic transcription factor Hoxa9. To our knowledge, this is the first mouse model of a SNP leading to epigenetic changes. Thus, SNPs not only result in an altered structure or expression level of certain proteins but here we show that SNPs might also lead to different cancer related epigenetic modifications. We used microarrays to detail the changes in the program of gene expression of GMPs induced by the knock in of human Gfi1 variants in the mouse Gfi1 locus Bone marrow derived granulocyte monocyte precursors (GMPs) from wt.-,Gfi1 knock-out.-, human Gfi1-knock in and human Gfi1-SNP36N knock in mice were collected by fluorescence activated cell sorting (FACS) for total RNA extraction and gene expression analysis on affymetrix mouse Gene 1.0 ST arrays. We aimed to identify differentially regulated target genes of the human Gfi1-SNP36N variant in a mouse model system which mit contribute to the development of acute myeloid leukemia (AML).
2012-11-22 | E-GEOD-25551 | biostudies-arrayexpress
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.
2023-12-01 | GSE195955 | GEO
Project description:Acute myeloid leukemia (AML) is characterized by accumulation of myeloid blast cells in the bone marrow. Despite all efforts, prognosis of AML patients remains poor, warranting new therapeutic approaches. A single nucleotide polymorphism of growth factor independence 1 (GFI1), a hematopoietic transcription factor, generates a protein with an asparagine (GFI136N) instead of a serine at position 36 (GFI136S), which we have previously reported to be associated with de novo AML in humans. Using knock-in mouse strains, in which the endogenous murine Gfi1 coding sequences are substituted by human GFI136N or GFI136S, we found that GFI136N shortened latency and increased incidence of AML in three different, well-established murine models of AML. On a molecular level, the presence of GFI136N was associated with increased acetylation of histone H3 at lysine 9 (H3K9) at Gfi1 target genes in both murine and human samples, contributing to AML development. Since in GFI136N containing leukemic cells Gfi1 target genes have hyperacetylated H3K9, the treatment strategy currently used with histone deacetylases inhibitors (HDACis) might not be beneficial. We show that treatment with an HDACi impeded growth of murine and human cells homozygous for GFI136S, but had a limited effect on cells expressing GFI136N. In contrast, treatment with a histone acetyltransferase inhibitor (HATi) specifically targeted GFI136N-expressing malignant cells while sparing non-malignant cells. These results establish, as a proof of principle, how epigenetic changes in GFI136N-induced AML can be exploited to treat AML and implicate HATi as a new, more effective potential therapeutic strategy for GFI136N AML patients.
2016-12-31 | GSE77073 | GEO
Project description:The incidence of cancer is not only influenced by exposure to environmental factors such as toxic substances and chemotherapy, but is also a result of individual predispositions. Single Nucleotide Polymorphisms (SNPs) represent one such individual predisposition to cancer1. Gfi136N is a SNP in the coding region of the gene “Growth factor independence 1 (Gfi1)” predisposing to development of Acute myeloid leukemia (AML). However, the mechanisms how this polymorphism is associated with AML are unknown. Here we present a mouse model in which the presence of Gfi136N leads to altered epigenetic modifications in the myeloid progenitor fraction “Granulocytic Monocytic Progenitor (GMP)” and demonstrates how this might predispose to AML. Presence of Gfi136N leads to a different epigenetic programming of the GMPs resulting in higher levels of the leukemogenic transcription factor Hoxa9. To our knowledge, this is the first mouse model of a SNP leading to epigenetic changes. Thus, SNPs not only result in an altered structure or expression level of certain proteins but here we show that SNPs might also lead to different cancer related epigenetic modifications. We used microarrays to detail the changes in the program of gene expression of GMPs induced by the knock in of human Gfi1 variants in the mouse Gfi1 locus
2012-11-22 | GSE25551 | GEO
Project description:Transcriptional repressor Growth factor independence 1 (GFI1) is a key regulator of haematopoiesis. We previously established that the germline variant GFI1-36N promotes acute myeloid leukemia (AML) development, however the mechanism is not full elucidated. Here using multi-omics approach, we show GFI1-36N expression impedes DNA repair in leukemic cells. We demonstrate 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) 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. Targeting MGMT via temozolomide and HR via olaparib caused specifically extensive lethality in in vitro and ex vivo human and AML samples expressing GFI1-36N. Whereas the effects were insignificant on non-malignant GFI1-36S or GFI1-36N cells. Further, mice transplanted with GFI1-36N leukemic cells treated with combination of temozolomide and olaparib had a significantly longer AML-free survival than mice transplanted with GFI1-36S leukemic cells. In summary, we show that GFI1-36N disturbs DNA repair activity via NDRG1-MGMT axis and thus provides critical insights into novel therapeutic option for AML presented with GFI1-36N variant. Key Points Presence of GFI1-36N impedes Homologous DNA and MGMT DNA repair selectively in AML cells via the NDRG1-MGMT axis. Use of temozolomide and olaparib allows selectively targeting GFI1-36N leukemic cells. Introduction Gfi1 is a transcription factor which regulates the development of haematopoietic cells as well as neuronal and intestinal epithelial cells 1-5. We reported that a variant of GFI1, denominated GFI1-36N (characterized by an exchange of serine to asparagine at position 36), has a prevalence of 5-7% in a healthy control population but is found at an increased frequency of 10-15% among MDS and AML patients 6,7. The expression of germline variant GFI1-36N predisposes the carriers to develop de novo AML and MDS and correlates with a poor prognosis 6,7. Recently, we and other showed that malignant cells with GFI1-36N variant have increased H3K9-acetylation at target genes resulting in higher expression of genes required for cell survival and proliferation 8. GFI1 exerts its repressive role by recruiting histone-modifying enzymes (deacetylases HDAC1-3, demethylase LSD1, methyl transferase G9a) and regulates the accessibility of DNA to its target genes such as Hoxa9, Pbx1, Meis1, CSF1 and CSFR1 9-15. We also showed that GFI1 regulates apoptosis through its regulation of p53 in lymphoblastic leukemia 16 and we have demonstrated that GFI1 facilitates DNA repair 17. However, it is not known how these activities are affected in the GFI1-36N variant and whether the ability of GFI1 to regulate DNA repair pathways is maintained and how this might affect the development of myeloid malignancies. In this study, we leveraged multi-omics profiling to gain mechanistic insights into the molecular architecture that drives leukemia in the presence of GFI1-36N. We provide evidence that GFI1-36N interferes with DNA in leukemic myeloid cells, which leads to a higher frequency of genetic aberrations in MDS/AML cells. We also show that GFI1-36N myeloid leukemic cells are more sensitive to targeting MGMT and HR repair deficient cells, which opens a new selective therapeutic window to treat AML/MDS.
2024-01-26 | PXD037433 | Pride
Project description:SAGA member Ada2 is required for the majority of H3K9 acetylation in C. neoformans. To identify specific genomic loci that exhibit Ada2-dependent H3K9 acetylation, we performed ChIP-Seq against H3K9ac in wildtype and ada2Δ cells. ChIP-Seq was performed using antibodies for H3K9ac in KN99 wildtype cells and ada2Δ cells. Input and IPed DNA was collected in triplicate from each strain and sequenced on an Illumnina HiSeq 2000 flow cell producing 84 million reads. Due to the lack of quality scores, raw reads are omitted from the submission.
2012-01-01 | E-GEOD-32075 | biostudies-arrayexpress