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Identification of a dynamic core transcriptional network in t(8 21) AML regulating differentiation block and self-renewal

ABSTRACT: Identification of a dynamic core transcriptional network in t(8 21) AML regulating differentiation block and self-renewal

PROVIDER: PRJNA257530 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR1145840_1.fastq.gz	Fastqsanger.gz
	SRR1145840_2.fastq.gz	Fastqsanger.gz
	SRR1145841_1.fastq.gz	Fastqsanger.gz
	SRR1145841_2.fastq.gz	Fastqsanger.gz
	SRR1145842_1.fastq.gz	Fastqsanger.gz

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Identification of a dynamic core transcriptional network in t(8;21) AML regulating differentiation block and self-renewal [ChIP-Seq]

Project description:The leukemogenic fusion protein RUNX1/ETO impairs myeloid differentiation and drives malignant self-renewal. Here we use digital footprinting and ChIP-sequencing to identify the core RUNX1/ETO responsive transcriptional network of t(8;21) cells. We show that the transcriptional programme underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind in a mutually exclusive fashion to identical genomic sites. Perturbation of this equilibrium by RUNX1/ETO knockdown results in a global reassembly of transcription factor complexes within pre-existing open chromatin and the formation of a new C/EBP-alpha-dominated transcriptional network driving myeloid differentiation. Our work demonstrates that the block in myeloid differentiation in t(8;21) is caused by the dynamic balance between RUNX1/ETO and RUNX1 activities and the repression of C/EBP-alpha and highlights the core targets of epigenetic reprogramming in t(8;21) AML. ChIP-sequencing and DNAse1-sequencing was used for the identification of a dynamic core transcriptional network in t(8;21) AML

2014-09-24 | E-GEOD-60130 | biostudies-arrayexpress

Identification of a dynamic core transcriptional network in t(8;21) AML regulating differentiation block and self-renewal [RNA-Seq]

Project description:The leukemogenic fusion protein RUNX1/ETO impairs myeloid differentiation and drives malignant self-renewal. Here we use digital footprinting and ChIP-sequencing to identify the core RUNX1/ETO responsive transcriptional network of t(8;21) cells. We show that the transcriptional programme underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind in a mutually exclusive fashion to identical genomic sites. Perturbation of this equilibrium by RUNX1/ETO knockdown results in a global reassembly of transcription factor complexes within pre-existing open chromatin and the formation of a new C/EBP-dominated transcriptional network driving myeloid differentiation. Our work demonstrates that the block in myeloid differentiation in t(8;21) is caused by the dynamic balance between RUNX1/ETO and RUNX1 activities and the repression of C/EBP and highlights the core targets of epigenetic reprogramming in t(8;21) AML. ChIP-sequencing, DNAse1-sequencing and RNA-sequncing was used for the identification of a dynamic core transcriptional network in t(8;21) AML This submission represents the RNA-Seq component of the study

2014-09-24 | E-GEOD-54478 | biostudies-arrayexpress

Identification of a dynamic core transcriptional network in t(8;21) AML regulating differentiation block and self-renewal [ChIP-Seq]

2014-09-24 | GSE60130 | GEO

Identification of a dynamic core transcriptional network in t(8;21) AML regulating differentiation block and self-renewal [RNA-Seq]

Project description:The leukemogenic fusion protein RUNX1/ETO impairs myeloid differentiation and drives malignant self-renewal. Here we use digital footprinting and ChIP-sequencing to identify the core RUNX1/ETO responsive transcriptional network of t(8;21) cells. We show that the transcriptional programme underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind in a mutually exclusive fashion to identical genomic sites. Perturbation of this equilibrium by RUNX1/ETO knockdown results in a global reassembly of transcription factor complexes within pre-existing open chromatin and the formation of a new C/EBP-dominated transcriptional network driving myeloid differentiation. Our work demonstrates that the block in myeloid differentiation in t(8;21) is caused by the dynamic balance between RUNX1/ETO and RUNX1 activities and the repression of C/EBP and highlights the core targets of epigenetic reprogramming in t(8;21) AML.

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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss

Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss

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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [RNA-seq]

Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [RNA-seq]

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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [ChIP-seq]

Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [ChIP-seq]

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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [ChIP-seq]

Project description:Acute myelogenous leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the mechanism underpinning the enhanced self-renewal conferred by cohesin haploinsufficiency. Using primary (HSPCs) as a model we demonstrate that a reduction in a core cohesin subunit is associated with decreased H3K27me3 and increased H3K79me2, along with increased self-renewal capacity and a leukemic transcriptional profile. Inhibition of DOT1L in cohesin-depleted HSPCs restored normal self-renewal, H3K27me3 and H3K79me2 levels, and gene expression, identifying DOT1L as a potential therapeutic target in cohesin haploinsufficient AML. Together our data further characterizes the mechanism by which cohesin mutations contribute to AML and identifies DOT1L as a potential therapeutic target for AML patients harboring cohesin mutations.

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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [RNA-seq]

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Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network

Project description:The embryonic stem (ES) cell transcriptional and epigenetic networks are critical for the maintenance of ES cell self-renewal. However, it remains unclear whether components of these networks functionally interact and if so, what factors mediate such interactions. Here we show that WD-repeat protein-5 (Wdr5), a core member of the mammalian Trithorax (trxG) complex, positively correlates with the undifferentiated state and is a novel regulator of ES cell self-renewal. We demonstrate that Wdr5, an ‘effector’ of H3K4 methylation, interacts with the pluripotency transcription factor Oct4. In concordance, genome-wide ChIP-Seq and transcriptome analyses demonstrate overlapping gene regulatory functions between Oct4 and Wdr5. We show that the Oct4-Sox2-Nanog circuitry cooperates with trxG for transcriptional activation of key self-renewal regulators. Furthermore, Wdr5 expression is required for the efficient formation of induced pluripotent stem (iPS) cells. Collectively, these findings implicate an integrated model of transcriptional and epigenetic control, mediated by select trxG members, for the maintenance of ES cell self-renewal and somatic cell reprogramming. 7 Samples

2011-04-08 | E-GEOD-22934 | biostudies-arrayexpress

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