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Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia [Cut&Tag]

ABSTRACT: Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia [Cut&Tag]

PROVIDER: PRJNA862548 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20653396_1.fastq.gz	Fastqsanger.gz
	SRR20653396_2.fastq.gz	Fastqsanger.gz
	SRR20653397_1.fastq.gz	Fastqsanger.gz
	SRR20653397_2.fastq.gz	Fastqsanger.gz

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Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia [RNA-seq]

Project description:The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a novel, computational machine learning application to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.

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Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia [Cut&Run]

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Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia [ATAC-seq]

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Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia [Cut&Tag]

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Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia [Capture Hi-C]

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Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia [APL PBMCs ATAC-seq]

Project description:The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We apply a novel computational deep learning strategy to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.

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PML-RARA fusion gene requires Dnmt3a to induce acute promyelocytic leukemia in mice

Project description:Loss of function mutations in the DNA methyltransferase DNMT3A are highly recurrent in acute myeloid leukemia (AML). DNMT3A and DNMT3B encode the two methyltransferases that are primarily responsible for the de novo methylation of specific DNA sequences during cellular differentiation. DNMT3A mutations are rarely found in AML patients with translocations that create oncogenic fusion genes (e.g. PML-RARA, RUNX1-RUNX1T1, CBFB-MYH11, and MLL-X). To begin to define the reasons why these mutations do not occur together, we used retroviral vectors to express PML-RARA, RUNX1-RUNX1T1, and MLL-AF9 in the bone marrow cells of wild type (WT) or Dnmt3a deficient mice; we also examined the hematopoietic phenotypes of Ctsg-PML-RARA animals (which express PML-RARA in early hematopoietic progenitors and myeloid precursors) with and without Dnmt3a. We demonstrated that the methyltransferase activity of Dnmt3a (but not Dnmt3b) is required for aberrant self-renewal ex vivo that is driven by PML-RARA (but not RUNX1-RUNX1T1 or MLL-AF9); furthermore, the PML-RARA-driven competitive transplantation advantage and leukemia generation both required Dnmt3a. Together, these findings demonstrate that PML-RARA is specifically dependent on Dnmt3a to initiate APL in mice, and may explain why loss-of-function DNMT3A mutations are not found in patients with acute promyelocytic leukemia.

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Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia

Project description:Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia

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mCG-PML-RARA alters multipotent hematopoiesis.

Project description:Acute promyelocytic leukemia (APL) is associated with PML-RARA expression and late myeloid maturation arrest. The myeloid restriction of PML-RARA dependent leukemia has been recapitulated in multiple mouse models of APL, including PML-RARA expressed from the Ctsg locus (mCG-PR). However, we report here that Ctsg expression is not limited to promyelocytes (as had previously been thought); Ctsg RNA is detectable in KLS cells, and mCG-PR mice express PML-RARA within the same compartment, an event that alters multilineage hematopoiesis. However, these animals only develop myeloid leukemia (consistent with the myeloid restriction of human PML-RARA-associated leukemia). Our results suggest that APL is shaped by myeloid- and development-specific factors that define the ultimate leukemic phenotype rather than PML-RARA acting in a committed myeloid precursor.

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Project description:PML/RARa is of crucial importance in acute promyelocytic leukemia (APL) both pathologically and therapeutically. Using a genome-wide approach, we identified in vivo PML/RARa binding sites in ZnSO4 treated PR9 cells. A total of 2,979 high quality binding sites were identified, representing 1,981 unique RefSeq genes. The supplementary bed file contains all 2,979 high quality PML-RARa binding sites reported in the paper.

2009-11-26 | GSE19202 | GEO

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