EYA1/SIX1/HOXA9 form a trimeric complex that sustains acute myeloid leukaemia
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ABSTRACT:
PROVIDER: PRJNA646306 | ENA |
REPOSITORIES: ENA
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Project description:Acute Myeloid Leukaemia (AML) is a highly heterogeneous disease characterised by an abnormal transcriptional landscape that results in a block in normal blood cell differentiation and aberrant self-renewal. Dysregulation of Homeobox A9 (HOXA9) expression is a hallmark of multiple AML subsets. Although HOXA9 is critical for maintaining leukaemic transformation, it has proven to be a challenging druggable target, and the underpinning molecular mechanisms through which it promotes leukaemogenesis remain elusive. Here, we report the existence of a tripartite complex between eyes absent 1 (EYA1), sine oculis homeobox 1 (SIX1) and HOXA9 in monocytic zinc finger (MOZ) and mixed-lineage leukaemia (MLL) rearranged AMLs. We employed ChIP-seq, together with RNA-seq, to identify regions bound and transcriptionally upregulated in a MOZ-TIF2 driven model of AML. Using RNA-seq, we demonstrated that EYA1 potentiates the transforming capacity of HOXA9 to confer a greater level of differentiation block via upregulation of Wnt and epithelial to mesenchymal transition (EMT) signalling cascades and suppression of myelo-monocytic programmes. We next sought to define the impact of pharmacologically destabilising the EYA1/SIX1/HOXA9 complex using Benzarone. Through a single cell RNA-Seq timecourse following treatment of MOZ-TIF2 cells with Benzarone, we provide evidence that disruption of EYA1 and its interactions results in differentiation of these cells. To prove the specificity of Benzarone towards EYA1, we also conducted RNA-Seq on cells expressing EYA1 and HOXA9 or HOXA9 alone.
2024-07-01 | GSE154447 | GEO
Project description:Otic ectoderm gives rise to almost all cell types of the inner ear; however, the mechanisms that link transcription factors, chromatin, lineage commitment and differentiation capacity are largely unknown. Here we show that Brg1 chromatin-remodeling factor is required for specifying neurosensory lineage in the otocyst and for inducing hair and supporting cell fates in the cochlear sensory epithelium. Brg1 interacts with the critical neurosensory-specific transcription factors Eya1/Six1, both of which simultaneously interact with BAF60a or BAF60c. Chromatin immunoprecipitation-sequencing (ChIP-seq) and ChIP assays demonstrate Brg1 association with discrete regulatory elements at the Eya1 and Six1 loci. Brg1-deficiency leads to markedly decreased Brg1 binding at these elements and loss of Eya1 and Six1 expression. Furthermore, ChIP-seq reveals Brg1-bound promoter-proximal and distal regions near genes essential for inner ear morphogenesis and cochlear sensory epithelium development. These findings uncover essential functions for chromatin-remodeling in the activation of neurosensory fates during inner ear development.
2020-04-17 | GSE119545 | GEO
Project description:Eya1 interacts with Six1/2 to induce nephron fate and promote nephron progenitor self-renewal. Haploinsufficiency for these genes in humans causes kidney agenesis or hypoplasia. However, how the Eya1-centered network operates remains elusive. Here we identify Eya1's interacting factors via mass-spectrometry and show that Eya1 and Six2 interact with Brg1-based SWI/SNF chromatin-remodeling complex in the kidney. Depletion of Brg1 results in lack of metanephric mesenchyme and depletion of nephron progenitor cells, which is linked to loss of Eya1 expression. Transcriptional profiling reveals conspicuous downregulation of the proto-oncogene Pbx1 and the Dchs1/Fat4 signaling but premature upregulation of a large subset of genes for podocyte lineages and aberrant activation of oncogenic factors in Brg1-deficent cell. ChIP-seq identifies Brg1-occupancy to enhancers at Pbx1 to a distal enhancer of Eya1 that drives nephron progenitor-specific expression. We demonstrate Six2-dependent Brg1 enrichment to the proximal-promoter of Mycn and two distal enhancers of Pbx1, all of which govern nephron progenitor-specific expression in response to binding to Six2. Together, our results suggest a possible mechanism through which the functional specificity of Brg1-BAFs and Eya1-Six2 in cell cycle regulation and self-renewal of the nephron progenitors may be in part achieved.
2021-10-01 | GSE185050 | GEO
Project description:HOXA9 and MEIS1 are essential downstream effectors of the MLL-AF9 oncoprotein during leukaemia induction. Leukaemia derived from MLL-AF9-transduced LSK cells has a more aggressive phenotype than that derived from HOXA9/MEIS1-transduced LSK cells. To determine differential gene expression that contributes to increased aggressiveness in MLL-AF9-induced leukaemia, microarray was performed on LSK cells transduced with MLL-AF9 versus HOXA/MEIS1 oncogenes.
2019-07-03 | E-MTAB-7355 | biostudies-arrayexpress
Project description:Specification of Sox2+ proneurosensory progenitors within otic ectoderm is a prerequisite for the production of sensory cells and neurons for hearing. However, the underlying molecular mechanisms driving this lineage specification remain unknown. Here, we show that Brg1-based SWI/SNF chromatin-remodeling complex interacts with the neurosensory-specific transcriptional regulators Eya1/Six1 to induce Sox2 expression and proneurosensory-lineage specification. Ablation of the ATPase-subunit Brg1 or both Eya1/Six1 results in loss of Sox2 expression and lack of neurosensory identity. Brg1 and Six1 co-occupy three distal 3' Sox2 enhancers and Brg1-recruitment to these regions is disrupted in Eya1- or Six1-null otocyst. Eya1 as a coactivator of Six1 synergistically regulates the activity of these enhancers, which drives expression in otic neurosensory cells in response to binding to Six1. Thus, through interaction with Six1/Eya1, the Brg1-based SWI/SNF complex specifies otic proneurosensory lineage. Furthermore, genome-wide and transcriptome analyses reveal that Brg1 also suppresses expression of non-otic genes.
2021-06-04 | GSE158167 | GEO
Project description:The vertebrate Six1 and Six2 arose by gene duplication from the Drosophila so (sine oculis) and have since diverged in their developmental expression patterns. Both genes are expressed in nephron progenitors of human fetal kidneys, and mutations in SIX1 or SIX2 cause branchio-oto-renal or renal hypodysplasia respectively. Since ~80% of SIX1 target sites are shared by SIX2, it is speculated that SIX1 and SIX2 may be functionally interchangeable by targeting common downstream genes. In contrast, in mouse kidneys, the expression of Six1 and Six2 only transiently overlaps in the metanephric mesenchyme before the onset of ureteric branching, and only Six2 expression is maintained in the nephron progenitors throughout development. This non-overlapping expression between Six1 and Six2 in mouse nephron progenitors promoted us to examine if Six1 can replace Six2. Surprisingly, forced expression of Six1 failed to rescue Six2-deficient kidney hypoplasia. We found that Six1 mediated Eya1 nuclear translocation and inhibited premature epithelialization of the progenitors but failed to rescue the proliferation defects and cell death caused by Six2-knockout. Genome-wide binding analyses showed that Six1 only bound to a small subset of Six2 target sites, but many Six2-bound loci that are crucial to the renewal and differentiation of nephron progenitors lacked Six1 occupancy. Thus, these data indicate that Six1 cannot substitute Six2 to drive nephrogenesis in mouse kidneys, demonstrating that these two transcription factors have not maintained equivalent biochemical properties since their divergence early in vertebrate evolution.
2022-01-27 | GSE189131 | GEO
Project description:Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and potential therapeutic interventions.
2024-08-08 | GSE224643 | GEO
Project description:Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and potential therapeutic interventions.
2024-08-08 | GSE260919 | GEO
Project description:SEM cells were established from the peripheral blood of a 5-year-old girl in relapse with acute lymphoblastic leukaemia (ALL). SEM cells exhibit the t(4;11) chromosomal rearrangement, which leads to production of the MLL-AF4 fusion protein. Hematopoietic transcription factors including HOXA9 and MEIS1 are highly expressed in ALL. ChIP-seq was performed against HoxA9 and MEIS1 in SEM cells. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing.
2012-05-31 | E-GEOD-38339 | biostudies-arrayexpress
Project description:To explore the spectrum of Eya1-interacting partner proteins, we thus generated a stable HEK293 cell line that constitutively express the 2HA–3FLAG-Eya1 (HF-Eya1) protein, purified HF-Eya1 from the cell extracts by a tandem affinity purification protocol to reduce background (first with anti-FLAG and then with anti-HA to purify FLAG-elute) and analyzed 12bands (B1-B12) using mass spectrometry.
2022-10-12 | PXD033955 | Pride