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Aberrant chromatin acetylation in MLL-AF9 leukemia mediates the response to HDAC inhibition (ChIP-Seq)

ABSTRACT: We studied the chromatin modification patterns induced by the presence of the MLL-AF9 fusion protein in a model of human hematopoietic stem/progenitor cells (HSPC) transduced with retrovirus expressing MLL-AF9cDNA (HSPC-MA9). Comparative ChIP-seq analysis between HSPC-MA9 and control HSPC, revealed a massive hyperacetylation of histones that was consistent with the transcriptional profile in the presence of MLL-AF9 fusion protein. Furthermore, we identified 66 MLL-AF9 targets, and found that H4ac was present along with H3K4me3 and H3K79me2 chromatin marks in over 50% of the MLL-AF9 target genes. Examination of histone aceylation and methylation changes upon expression of MLL-AF9 fusion protein in human hematopoietic stem/progenitor cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Sara Alvarez

PROVIDER: E-GEOD-54344 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Aberrant chromatin acetylation in MLL-AF9 leukemia mediates the response to HDAC inhibition (microarray)

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Aberrant chromatin acetylation in MLL-AF9 leukemia mediates the response to HDAC inhibition (ChIP-Seq)

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scRNA-seq of control and eIF6-overexpressing MLL-AF9 leukemia stem cells

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2015-03-01 | GSE54218 | GEO

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Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential

Project description:The MLL gene is a common target of chromosomal translocations found in human leukemia. MLL-fusion leukemias are consistently poor prognosis. One of the most common translocation partners is AF9 (a.k.a. MLLT3). MLL-AF9 recruits DOT1L, a histone 3 lysine 79 methyltransferase (H3K79me1/me2/me3), leading to aberrant gene transcription. We show that DOT1L has three AF9 binding sites, and present the NMR solution structure of a DOT1L-AF9 complex. We generated structure-guided point mutations with graded effects on recruitment of DOT1L to MLL-AF9. ChIP-Seq analyses of H3K79me2 and H3K79me3 show that graded reduction of the DOT1L interaction with MLL-AF9 results in selective losses in H3K79me2 and me3 marks at MLL-AF9 target genes. Furthermore, the degree of DOT1L recruitment defines the level of MLL-AF9 hematopoietic transformation. Hematopoietic progenitor cells isolated from mouse bone marrow were transduced with retrovirus expressing either wildtype MLL-AF9 (WT), mutants, MLL-AF9 (D544R) and MLL-AF9 (D546R). ChIP-Seq analyses were performed on these wildtype and mutant cells using H3K79me2 and H3K79me3 antibodies. 3 samples corresponding to ChIP-Seq with H3K79me2 antibody: 1) MLL-AF9 (WT) 2) MLL-AF9 (D544R) 3) MLL-AF9 (D546R) 3 Samples Corresponding to ChIP-Seq with H3K79me3 antibody: 4) MLL-AF9 (WT) 5) MLL-AF9 (D544R) 6) MLL-AF9 (D546R)

2015-04-30 | E-GEOD-64365 | biostudies-arrayexpress

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