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MLL1 and MLL fusion proteins play distinct roles in regulating MLLleukemic transcription program [ChIP-Seq]

ABSTRACT: This study describes the epigenetic profiling change of 1.) Mll1, WDR5 and H3K4me2 in mouse MAF9 leukemia cells treated with or without MM401; 2.) WDR5 and H3K4me2 epigenetic profiling in MLL1 flox/flox, ER-Cre+/- cells with knocking out MLL1 by 4OHT or not.

ORGANISM(S): Mus musculus

PROVIDER: GSE68821 | GEO | 2016/05/12

SECONDARY ACCESSION(S): PRJNA283891

REPOSITORIES: GEO

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ChIP-chip of siGFP- or siHOTTIP-treated foreskin fibroblasts with anti-H3K4me3, anti-H3K27me3, anti-H3K4me2, anti-histone, anti-MLL1, and anti-WDR5 antibodies on HOX tiling array

Project description:Coordinate loss of MLL1 and WDR5 occupancy caused by HOTTIP knockdown were observed in distal HOXA genes. These regions correspondingly lost H3K4me3 and H3K4me2, without changes in pan-histone or H3K27me3. human foreskin fibroblasts (CRL2091), anti-H3K4me3 (Abcam ab8580, lot#1016899), anti-H3K4me2 (Abcam ab32356, lot#947550), anti-H3K27me3 (Abcam ab4729, lot#1021724), anti-histone H3 (Abcam ab1791, lot#1025144), anti-MLL1 (gift of R. Roeder, Rockefeller University), and anti-WDR5 (gift of W. Herr, UNIL) Comparison of occupancy of MLL1 and WDR5 of siGFP and siHOTTIP foreskin fibroblasts on HOX tiling array. Human foreskin fibroblasts are transfected with siGFP or siHOTTIP for 72 hrs. The cells are harvesed and ChIP performed with H3K4me3, H4K27me3, H3K4me2, MLL1, WDR5, and histone antibodies.

2011-03-21 | E-GEOD-26540 | biostudies-arrayexpress

ChIP-chip of siGFP- or siHOTTIP-treated foreskin fibroblasts with anti-H3K4me3, anti-H3K27me3, anti-H3K4me2, anti-histone, anti-MLL1, and anti-WDR5 antibodies on HOX tiling array

2011-03-21 | GSE26540 | GEO

MLL1 and MLL fusion proteins play distinct roles in regulating MLLleukemic transcription program [RNA-Seq]

Project description:This study describes the transcriptome profiling of: 1) MM-401, a MLL1 specific inhibitor in MAF9 cells; 2) Comparation of the transcriptone profilings of MM-401,EPZ-5676 (Dot1L inhibitor), MI-2(Menin inhibitor) and iBET(Brd4 inhibitor) in MAF9 leukemia cells.

2016-05-12 | GSE68822 | GEO

MLL1 and MLL fusion proteins play distinct roles in regulating MLLleukemic transcription program

Project description:MLL1 and MLL fusion proteins play distinct roles in regulating MLLleukemic transcription program

| PRJNA283883 | ENA

Unraveling MLL1-fusion Leukemia: Epigenetic Revelations from an iPS Cell Point Mutation

Project description:This SuperSeries is composed of the SubSeries listed below. Our understanding of acute leukemia pathology is heavily dependent on 11q23 chromosomal translocations involving the mixed lineage leukemia-1 (MLL1) gene, a key player in histone H3 lysine 4 (H3K4) methylation. These translocations result in distinct MLL1-fusion (MLL1F) proteins that are thought to drive leukemogenesis. However, the mechanism behind increased H3K4 trimethylation in MLL1F-leukemic stem cells (MLL1F-LSCs), following loss of catalytic SET domain of MLL1 (known for H3K4 mono- and dimethylation), remains unclear. In our investigation, we introduced a homozygous loss-of-function point mutation in MLL1 within human induced pluripotent stem cells. Remarkably, this mutation mimics the histone methylation, gene expression, and EMT phenotypes of MLL1F-LSCs- without the need for a translocation or functional wild-type MLL1. This observation underscores the essential role of MLL1's enzymatic activity in restraining the cascade of epigenetic changes associated with the gene activating H3K4 trimethylation mark, which we show is catalyzed by mislocalized SETd1a H3K4 trimethyltransferase in the absence of MLL1’s enzymatic activity. Challenging existing models, our findings imply that MLL1F-induced leukemias arise from a dominant-negative impact on MLL1's histone methyltransferase activity. We advocate for a therapeutic paradigm shift, targeting SETd1a for precision medicine. This work opens new avenues for addressing the complexities of MLL1-associated leukemias and improving targeted therapies.

2024-09-09 | GSE213239 | GEO

Genome-wide maps of NUP98 fusion and MLL1 co-bound targets and their chromatin state in NUP98 fusion transformed cells.

Project description:By performing biotin-mediated chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) for two different NUP98 fusions, we defined the genome-wide direct binding sites of NUP98-HOXA9 or NUP98-HOXD13. To test whether NUP98 fusions and Mll1 were recruited to the same region of Hox genes promoters, Mll1 ChIP-seq analysis was carried out in murine NUP98-HOXA9 transformed cells using an anti-Mll1n antibody. In agreement with our results showing that NUP98-HOXA9 interacts with MLL1 in NSL/MLL1 complex, Mll1 binding targets significantly overlap with that of NUP98-HOXA9 at promoter region and gene body region. Given that MOF and MLL1 work in concert to modify H4K16ac and H3K4me3 at promoters, we further test whether H3K4me3 and H4K16ac marks are associated with NUP98-HOXA9-bound targets in murine NUP98-HOXA9 transformed cells by anti-H3K4me3 and anti-H4K16ac ChIP-seq. Our data show that both H3K4me3 and H4K16ac mark presents on NUP98-HOXA9 binding targets at promoters, and this is in line with the coordination role in the activities between MOF-mediated H4K16 acetylation and MLL/SET-mediated H3K4 methylation. In summary, our results confirmed that NUP98-HOXA9 and Mll1 are recruited to the same Hox loci, and this recruitment is associated with activating epigenetic marks, supporting the notion of the association between NUP98 fusions and NSL/Mll1 complex, suggesting that the recruitment of NUP98 fusions to the Hox gene loci maybe through MLL1.

2016-12-11 | GSE76001 | GEO

Unannotated microprotein EMBOW switches WDR5 between epigenetic and mitotic roles during cell cycle

Project description:The highly conserved WD40-repeat protein WDR5 is part of multiple functional complexes both inside and outside the nucleus, interacting with the MLL/SET1 histone methyltransferases that catalyze histone H3 lysine 4 (H3K4) di- and tri-methylation (me2,3), and KIF2A, a member of the Kinesin-13 family of microtubule depolymerase. It is currently unclear whether, and how, the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein dually encoded in the human SCRIB gene regulates the association of WDR5 with epigenetic and KIF2A complexes. We propose to name this alt-protein EMBOW, or microprotein that is the epigenetic to mitotic binder of WDR5. Loss of EMBOW decreases WDR5 interaction with KIF2A, displaces WDR5 from the spindle pole during G2/M phase, and shortens the spindle length, hence prolonging G2/M phase and delaying cell proliferation. On the other hand, loss of EMBOW increases WDR5 interaction with epigenetic complexes, including KMT2A/MLL1, and promotes WDR5 association with chromatin and binding to the target genes, hence increasing H3K4me3 levels of target genes. Together, these results implicate EMBOW as a regulator of WDR5 that switches it between epigenetic and mitotic regulatory roles during cell cycle, explaining how mammalian cells can temporally control the multifunctionality of WDR5.

2023-09-19 | PXD036699 | Pride

MLL1 and MLL fusion proteins play distinct roles in regulating MLLleukemic transcription program

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-05-12 | GSE68823 | GEO

Genome binding/occupancy profiling of Mll1 in mouse embryo stem cells

Project description:This study describes the epigenetic profiling of Mll1 in mouse ES cells cultures in LIF/serum/feeder-free condition. ChIP-Seq profile of Mll1 was generated in E14Tg2a (E14) mESCs. A sequence profile of genomic DNA (Input) is also included.

2016-02-19 | E-GEOD-66111 | biostudies-arrayexpress

Expression analysis on Mll1+/+ and Mll1-/- MEFs

Project description:Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. The Set1/COMPASS was the founding member and the only H3K4 methylases in S. cerevisiae, however, in mammals at least six H3K4 methylases Set1A/B and MLL1-4 are found in COMPASS-like complexes capable of methylating H3K4. To gain further insight into the different roles and functional targets for the H3K4 methylases, we have undertaken a genome-wide analysis of H3K4 methylation pattern in wild-type Mll1+/+ and Mll1-/- mouse fibroblasts (MEFs). We found that Mll1 is required for the H3K4 trimethylation of less than 5% of promoters carrying this modification. Many of these genes, which include developmental regulators such as Hox genes show decreased levels of RNA polymerase II recruitment and expression concomitant with the loss of H3K4 methylation. Although Mll1 is only required for the methylation of a subset of Hox genes, Menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/4 and/or the Set1 complexes have little to no effect on the Hox loci H3K4 methylation or expression levels in these MEFs. Together these data provide insight into redundancy and specialization of COMPASS-like complexes in mammals and provide evidence on a possible role for Mll1-mediated H3K4 methylation in the regulation of transcriptional initiation. Expression arrays were done with Mll1+/+ and Mll1-/- mouse embryonic fibroblasts. Four replicates were done (dyes were swapped). DNA was hybridized to Agilent Mouse Whole Genome Expression Arrays (4x44k).

2009-10-20 | E-GEOD-18261 | biostudies-arrayexpress

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