Single cell analysis of MNX1 overexpression in hemogenic gastruloids
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB56088 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| ERR10201400_1.fastq.gz | Fastqsanger.gz | |||
| ERR10201400_2.fastq.gz | Fastqsanger.gz | |||
| ERR10201500_1.fastq.gz | Fastqsanger.gz | |||
| ERR10201500_2.fastq.gz | Fastqsanger.gz |
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Project description:The t(7;12) AML subtype in pediatric patients is associated with upregulation of homeodomain protein MNX1 as the initiating event for leukemogenesis. In this study, we investigated the downstream targets of MNX1 and their relationship to the histone modifications previously observed to be mediated by MNX1. Using a comprehensive approach combining TMT mass spectrometry, RNA-Seq, qPCR, ACT-seq, ATAC-seq, and ChIP-qPCR, we identified PBXIP1 along with its associated pioneer transcription factor PBX1 and PBX4 as downstream targets of MNX1. MNX1 binding to the Pbx1 promoter triggered its transcriptional activation, which was associated with an increase in the activating histone mark H3K4me3 and a decrease in the repressive mark H3K27me3 at the promoter site. Notably, despite the transient nature of MNX1’s promoter interaction, these histone marks persisted, suggesting a “hit-and-run” epigenetic remodeling mechanism. Enrichment of PBX motifs within MNX1-induced H3K4me1, H3K4me3, and ATAC-seq peaks underscores the pivotal role of the PBX family in MNX1-mediated chromatin dynamics. This was further confirmed by showing that MNX1-induced PBX1 expression could be downregulated using the Sinefungin inhibitor, a pan-methyltransferase inhibitor, that also prevent leukemia development. Our findings provide insights into how MNX1-driven epigenetic modifications are connected to its downstream targets and may offer new avenues for therapeutic intervention in t(7;12) AML.
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Project description:Recently we have identified the upregulation of the homebox domain protein MNX1 associated with the paediatric t(7;12) AML as the initiating event for Leukaemia in mice. We demonstrated that MNX1 triggers abnormal histone modifications, specifically H3K4me3 and H3K27me3, by interacting with SAM-dependent methyltransferases. In the current study our aim was investigate downstream targets of MNX1 and the relationship with histone modification. Employing TMT Mass spectrometry and RNA-Seq integrative analysis identified the pioneer transcription factor PBX1 as a downstream target of MNX1. We observe that MNX1 binds to the promoter region of PBX1, leading to increased expression of PBX1. This binding of MNX1 to the PBX1 promoter was associated with enhanced H3K4me3 and decreased H3K27me3 in the same promoter region. Interestingly, this binding of MNX1, but not the histone modification on the PBX1 promoter was transient and diminishes as MNX1-FL cells progress to leukaemia in mice. To gain further insight, we conducted a comparative analysis of H3K4me3 using ACT-Seq and RNA-Seq data between MNX preleukemia FL cells and leukaemia MNX1 BM blasts. Our results indicate that this phenomenon is not limited to PBX1 but is rather widespread throughout the genome, identifying several downstream targets for MNX1 mediated H3K4me3 modification. Investigating the PBX1 and 4 motifs identified from Chip-Seq, revealed a significant enrichment in MNX1 H3K4me3 and ATAC-seq peaks. This suggest that PBX family might play an important role in the function of MNX1, which was further confirmed by showing MNX1 induced PBX1 expression to be downregulated using the sinefungin inhibitor, which we have previously reported to inhibit leukemia induction by MNX1.
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