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An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX [ChIP-seq re-analysis]

ABSTRACT: An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX [ChIP-seq re-analysis]

PROVIDER: PRJNA936113 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23508110_1.fastq.gz	Fastqsanger.gz
	SRR23508110_2.fastq.gz	Fastqsanger.gz
	SRR23508111_1.fastq.gz	Fastqsanger.gz
	SRR23508111_2.fastq.gz	Fastqsanger.gz
	SRR23508112_1.fastq.gz	Fastqsanger.gz

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An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX [4C-seq]

Project description:In acute myeloid leukaemia (AML), abnormal self-renewal and proliferation of a cell population defined as leukaemia stem cells (LSCs) results in the accumulation of undifferentiated blast cells in the bone marrow and blood. Gene expression analyses comparing LSCs to healthy haematopoietic stem cells (HSCs) revealed a significant upregulation of the transcription factor IRX3 in the LSC compartment, and functional experiments demonstrated that IRX3 contributes to a block in differentiation. Interestingly, IRX3 is minimally expressed in HSCs and not required for normal haematopoietic development. These discoveries highlight the necessity to investigate mechanisms underlying IRX3 misexpression in AML, as well as further investigate the mechanisms through which IRX3 expression contributes to the differentiation block. To investigate the mechanism of IRX3 misexpression in AML, we applied long-range chromatin interaction analyses, genome editing, enhancer-function studies and diverse bioinformatics tools in both AML cell lines and primary patient samples. We characterise for the first time a cluster of bona-fide enhancers and its associated transcript (eRNA), and describe a model through which these regulatory elements contribute to IRX3 expression. The cluster is composed of four modules with IRX3-regulatory activity in AML cells. Moreover, transcripts arise from the E2 module and aids in the function of the super-enhancer by falicitating a chromatin loop with the IRX3 promoter and maintaining high levels of H3K27ac at both the enhancer modules and IRX3 promoter.

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An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX [MeDIP-seq re-analyzed]

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An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX

Project description:An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX

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Obesity-associated variants within FTO form long-range functional connections with IRX3

Project description:Genome-wide association studies in diverse populations have reproducibly associated variants within introns of FTO with increased risk for obesity and type-2 diabetes.While the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. Yet, no direct connection between the obesity-associated intronic variants and FTO expression or function has been made. We show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, primarily with the homeobox gene IRX3, rather than with FTO. 4C-seq samples for Fto/fto and Irx3/irx3a genes promoters in different samples: adult mouse brain, E9.5 mouse embryos and 24hpf zebrafish embryos.

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An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX [RNA-Seq]

Project description:An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX [RNA-Seq]

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An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX [4C-seq]

Project description:An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX [4C-seq]

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Project description:An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX [RNA-seq re-analysis]

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An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX [MeDIP-seq re-analyzed]

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