Three-dimensional chromatin landscapes in MLLr AML [Micro-C]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE244471 | GEO | 2024/02/20
REPOSITORIES: GEO
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Project description:Rearrangements of the mixed lineage leukemia (MLLr) gene are frequently associated with both pediatric and adult leukemia. However, the treatment options for these aggressive MLLr leukemias are limited due to the genomic complexity and dynamics of 3D structure in oncogene transcription and leukemia development. Here, we use Micro-C and transcriptome profiling to examine the MLLr-driven aberrant 3D genome architecture in gene-edited MLL-AF9 AML samples with biologically matched healthy donors. Recurrent and MLLr-specific alterations in A/B compartments, topologically associating domains and chromatin loops were identified. RNA sequencing in the same AML samples also revealed extensive and recurrent MLLr-specific promoter–enhancer and promoter–silencer loops. Overall, this study highlights the critical regulatory elements and provides rational and effective targeting strategy in MLLr AML.
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Project description:Acute myeloid leukemia (AML) is a set of heterogeneous myeloid malignancies hallmarked by mutations in epigenetic modifiers, transcription factors and kinases that can cause epigenetic reshaping. It is unclear whether those mutations drive chromatin 3D structure alteration and contribute to oncogenic dysregulation in AML. By performing Hi-C and whole genome sequencing in 21 primary AML and healthy donors’ samples, we identified recurrent AML- or subtype-specific alteration of compartments, TADs, and chromatin loops. To study the impact on gene regulation, we performed RNA-Seq, ATAC-Seq and CUT&TAG for CTCF, H3K27ac, and H3K27me3 in the same samples. We observed dysregulation of many AML-related genes, represented by MYCN, MEIS1, WT1, ERG, MYC GATA3, BCL11B and IKZF2, intimately linked to the recurrent gain of loops and switch of compartment or TAD, alongside acquisition of AML-specific enhancer or repressor. Further, we profiled structure variations using WGS and Hi-C data to reconstruct the cancer 3D genome, by which we identified structure variation-induced neo-loops and enhancer-hijacking events. Furthermore, through conducting whole genome bisulfite sequencing in patient samples, we found altered methylation correlated with A/B compartment switch, and loss of CTCF insulation due to hypermethylation, leading to extensive gain of loops in AML. By treating the AML cells with DNA hypomethylation agent 5-azacytidine, the altered chromatin structure and gene expression can be restored, with switched compartment reverted and gained loops dissociated, alongside compromised AML cell proliferation, overall providing insights into AML treatment through therapeutic restoration of chromatin structure.
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Project description:Acute myeloid leukemia (AML) is a set of heterogeneous myeloid malignancies hallmarked by mutations in epigenetic modifiers, transcription factors and kinases that can cause epigenetic reshaping. It is unclear whether those mutations drive chromatin 3D structure alteration and contribute to oncogenic dysregulation in AML. By performing Hi-C and whole genome sequencing in 21 primary AML and healthy donors’ samples, we identified recurrent AML- or subtype-specific alteration of compartments, TADs, and chromatin loops. To study the impact on gene regulation, we performed RNA-Seq, ATAC-Seq and CUT&TAG for CTCF, H3K27ac, and H3K27me3 in the same samples. We observed dysregulation of many AML-related genes, represented by MYCN, MEIS1, WT1, ERG, MYC GATA3, BCL11B and IKZF2, intimately linked to the recurrent gain of loops and switch of compartment or TAD, alongside acquisition of AML-specific enhancer or repressor. Further, we profiled structure variations using WGS and Hi-C data to reconstruct the cancer 3D genome, by which we identified structure variation-induced neo-loops and enhancer-hijacking events. Furthermore, through conducting whole genome bisulfite sequencing in patient samples, we found altered methylation correlated with A/B compartment switch, and loss of CTCF insulation due to hypermethylation, leading to extensive gain of loops in AML. By treating the AML cells with DNA hypomethylation agent 5-azacytidine, the altered chromatin structure and gene expression can be restored, with switched compartment reverted and gained loops dissociated, alongside compromised AML cell proliferation, overall providing insights into AML treatment through therapeutic restoration of chromatin structure.
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Project description:Acute myeloid leukemia (AML) is a set of heterogeneous myeloid malignancies hallmarked by mutations in epigenetic modifiers, transcription factors and kinases that can cause epigenetic reshaping. It is unclear whether those mutations drive chromatin 3D structure alteration and contribute to oncogenic dysregulation in AML. By performing Hi-C and whole genome sequencing in 21 primary AML and healthy donors’ samples, we identified recurrent AML- or subtype-specific alteration of compartments, TADs, and chromatin loops. To study the impact on gene regulation, we performed RNA-Seq, ATAC-Seq and CUT&TAG for CTCF, H3K27ac, and H3K27me3 in the same samples. We observed dysregulation of many AML-related genes, represented by MYCN, MEIS1, WT1, ERG, MYC GATA3, BCL11B and IKZF2, intimately linked to the recurrent gain of loops and switch of compartment or TAD, alongside acquisition of AML-specific enhancer or repressor. Further, we profiled structure variations using WGS and Hi-C data to reconstruct the cancer 3D genome, by which we identified structure variation-induced neo-loops and enhancer-hijacking events. Furthermore, through conducting whole genome bisulfite sequencing in patient samples, we found altered methylation correlated with A/B compartment switch, and loss of CTCF insulation due to hypermethylation, leading to extensive gain of loops in AML. By treating the AML cells with DNA hypomethylation agent 5-azacytidine, the altered chromatin structure and gene expression can be restored, with switched compartment reverted and gained loops dissociated, alongside compromised AML cell proliferation, overall providing insights into AML treatment through therapeutic restoration of chromatin structure.
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