Role of H3K79 methylation states in HOX gene expression and leukemogenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Scott Armstrong
PROVIDER: E-GEOD-54500 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:We wanted to investigate the effects of Dot1l deletion on gene expression in LSKs and GMPs of C57/BL6 mice Aberrant Hox gene activation is a recurrent feature in several different types of human leukemia, including leukemias with rearrangements of the mixed lineage leukemia (MLL) gene. In this study, we demonstrate that Hox gene expression is controlled by higher degree H3K79 methylation in acute myeloid leukemia (AML). We show that the deposition of progressive H3K79 methylation states at the genomic loci of critical Hox genes is dependent on the interaction of the H3K79 methyltransferase Dot1l with Af10, a protein that is found in the Dot1l complex isolated from diverse cell types. Furthermore, abrogation of the Dot1l-Af10 interaction reverses aberrant epigenetic profiles found in the leukemia epigenome and impairs the transforming ability of mechanistically distinct AML oncogenes. Lineage negative Sca-1 positive Kit positive (LSK) cells and granulocyte macrophage progenitors (GMPs) were sorted from Dot1 wt/wt x Mx-Cre mice or Dot1l fl/fl x Mx-Cre mice were injected with PIPC. PIPC injection induced biallelic deletion of the Dot1l allele in the Dot1l fl/fl mice but not the Dot1l wt/wt mice. The Dot1l wt/wt LSKs and GMPs were compared to the Dot1l -/- counterparts by RNA extraction and Microarrays.
2014-09-08 | E-GEOD-54498 | biostudies-arrayexpress
Project description:Aberrant Hox gene activation is a recurrent feature in several different types of human leukemia, including leukemias with rearrangements of the mixed lineage leukemia (MLL) gene. In this study, we demonstrate that Hox gene expression is controlled by higher degree H3K79 methylation in acute myeloid leukemia (AML). We show that the deposition of progressive H3K79 methylation states at the genomic loci of critical Hox genes is dependent on the interaction of the H3K79 methyltransferase Dot1l with Af10, a protein that is found in the Dot1l complex isolated from diverse cell types. Furthermore, abrogation of the Dot1l-Af10 interaction reverses aberrant epigenetic profiles found in the leukemia epigenome and impairs the transforming ability of mechanistically distinct AML oncogenes. Primary MLL-AF9 leukemias in the AF10 floxed background (homozygous) were transduced with MSCV-IRES-tdTomato (MIT) or the Cre recombinase expressing MIT vector, cells were sorted and injected into secondary recipient mice to generate Af10 floxed (MIT) or deleted (CRE) leukemias. BM cells fresly harvested from these leukemias were sorted for tdTomato expression and used for microarrays. BM cells from Hoxa9-Meis1 transduced primary leukemias were used for comparison.
2014-09-08 | E-GEOD-54499 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-04-03 | E-GEOD-43069 | biostudies-arrayexpress
Project description:Transcription factors are key regulators of hematopoieticstem cells (HSCs) and act through their ability to bind DNA andimpact on gene transcription. Their functions are interpreted inthe complex landscape of chromatin but current knowledge on howthis is achieved is very limited. C/EBPa is an importanttranscriptional regulator of hematopoiesis, but its potentialfunctions in HSCs have remained elusive. Here we report that C/EBPaserves to protect adult HSCs from apoptosis and to maintain theirquiescent state. Consequently, deletion of Cebpa is associatedwith loss of self-renewal and HSC exhaustion. By combining geneexpression analysis with genome-wide assessment of C/EBPa bindingand epigenetic configurations, we show that C/EBPa acts tomodulate the epigenetic states of genes belonging to molecularpathways important for HSC function. Moreover, we demonstrate thatC/EBPa acts as a priming factor at the HSC level to activelypromote myeloid differentiation and counteract lymphoid lineagechoice. Taken together our results show that C/EBPa is a keyregulator of HSC biology, which influences the epigeneticlandscape of HSCs in order to balance different cell fate options. C/EBPaplha binding was assesed in heamatopoietic stem- and progenitor cells (LSK) and in myeloid progenitor cells (GMP) using ChIP-seq
2013-12-01 | E-GEOD-43007 | biostudies-arrayexpress
Project description:The capacity of the hematopoietic system to promptly respond to peripheral demands relies on adequate pools of progenitors able to transiently proliferate and differentiate in a regulated manner. However, little is known about factors that may restrain progenitor maturation to maintain their reservoirs. In addition to a profound defect in hematopoietic stem cell (HSC) self-renewal, conditional knockout mice for the Pbx1 proto-oncogene have a significant reduction in lineage-restricted progenitors, including common myeloid progenitors (CMPs) and, to a lesser extent, granulocyte-monocyte progenitors (GMPs). Through analysis of purified progenitor proliferation, differentiation capacity and transcriptional profiling, we demonstrate that in the absence of Pbx1 the CMP pool is reduced due to aberrantly rapid myeloid maturation, associated with decreased expression of Meis1 and its targets including Flt3. BM cells were obtained from multiple bones of individual three to five week old Tie2Cre+.Pbx1-/f or Tie2Cre+.Pbx1+/f control mice (4-5 biological replicates/group). CMPs and GMPs were sorted by flow cytometry according to the following markers: Lin-/c-Kit+/Sca-/CD34+/CD16/32int, and Lin-/c-Kit+/Sca-/CD34+/CD16/32high, respectively, prior to RNA extraction.
2013-03-31 | E-GEOD-30028 | biostudies-arrayexpress
Project description:The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in MLL-AF9 AML. We evaluated the dependance on beta-catenin for KrasG12DMLL-AF9 leukemia. Lin-Kit+ bone marrow cells obtained from mice transplanted with primary MLL-AF9 leukemia cells and KRasG12DMLL-AF9 leukemia cells were assessed for gene expression in the presence or absence of beta-catenin
2014-07-02 | E-GEOD-49248 | biostudies-arrayexpress
Project description:MLL-fusions may induce leukemogenic gene expression programs by recruiting the histone H3K79 methyltransferase to MLL-target promoters. We evaluated gene expression changes after cre-mediated loss of Dot1l in leukemia cells obtained from mice injected with MLL-9 transformed lineage negative bone marrow cells. MLL-AF9 murine leukemia cells carrying two conditional Dot1l alleles were retrovirally transduced with Cre or empty control vector, and gene expression changes were monitored on day 3, 5, and 7 after transduction.
2011-09-12 | E-GEOD-25911 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE34959: Expression profiling of primary wild type (WT), Ezh2-null and Eed-null murine MLL-AF9 AML GSE34961: Expression profiling of secondary wild type (WT) and Ezh2-null murine MLL-AF9 AML GSE34962: Epigenetic profiling of WT and Ezh2-null MLL-AF9 murine leukemic cells Refer to individual Series
2012-02-22 | E-GEOD-34963 | biostudies-arrayexpress
Project description:The MLL gene on chromosome 11 fuses to the AF6 gene on chromosome 6 in a balanced chromosomal translocation that is characetristic of certain adult and pediatric human leukemias. We established a murine leukemia model of MLL-AF6 using the retroviral MLL-AF6 contruct in a bone marrow transplantation system. Leukemic bone marrow cells from a sacrificed moribund mouse were thawed and RNA was extracted using TRIZOL (Invitrogen) and purified further using the RNAeasy kit (Qiagen) under standard conditions and and hybridized onto Affymetrix arrays.
2013-04-03 | E-GEOD-43067 | biostudies-arrayexpress
Project description:The MLL gene on chromosome 11 fuses to the AF6 gene on chromosome 6 in a balanced chromosomal translocation that is characetristic of certain adult and pediatric human leukemias. We established a murine leukemia model of MLL-AF6 using the retroviral MLL-AF6 contruct in a bone marrow transplantation system. The ML2 human MLL-AF6 positive leukemia cell line was used for gene expression profiling to assess the transctiptional profile in MLL-AF6 leukemias. RNA was extracted from the ML2 cell line cultured under standard conditionswith TRIZOL (Invitrogen), purified using RNAeasy(Qiagen) and hybridized onto Affymetrix arrays.
2013-04-03 | E-GEOD-43068 | biostudies-arrayexpress