Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

The Growth factor independence 1 (GFI1) 36N variant predisposes to Acute Myeloid Leukemia (AML) by inducing epigenetic changes at the Hoxa9 locus

ABSTRACT: 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)

ORGANISM(S): Mus musculus

SUBMITTER: Judith Schütte

PROVIDER: E-GEOD-31657 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice.

Khandanpour Cyrus C Krongold Joseph J Schütte Judith J Bouwman Frederique F Vassen Lothar L Gaudreau Marie-Claude MC Chen Riyan R Calero-Nieto Fernando J FJ Diamanti Evangelia E Hannah Rebecca R Meyer Sara E SE Grimes H Leighton HL van der Reijden Bert A BA Jansen Joop H JH Patel Chandrashekhar V CV Peeters Justine K JK Löwenberg Bob B Dührsen Ulrich U Göttgens Bertie B Möröy Tarik T

Blood 20120828 19

The coding single nucleotide polymorphism GFI136N in the human gene growth factor independence 1 (GFI1) is present in 3%-7% of whites and increases the risk for acute myeloid leukemia (AML) by 60%. We show here that GFI136N, in contrast to GFI136S, lacks the ability to bind to the Gfi1 target gene that encodes the leukemia-associated transcription factor Hoxa9 and fails to initiate histone modifications that regulate HoxA9 expression. Consistent with this, AML patients heterozygous for the GFI13 ...[more]

PMID: 22932805

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Project description:Whole genome profiling of 4 histone modifications (H3K27me1, H3K27me3,H3K36me1 and H3K36me3) using ChIP-on-chip. It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons ("exon-intron marking"), linking chromatin structure and function to co- transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing.

Dataset Information

The Growth factor independence 1 (GFI1) 36N variant predisposes to Acute Myeloid Leukemia (AML) by inducing epigenetic changes at the Hoxa9 locus

Publications

The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice.

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