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C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions

ABSTRACT: C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions

PROVIDER: PRJNA991944 | ENA |

REPOSITORIES: ENA

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C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions [RNA-Seq]

Project description:C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions [RNA-Seq]

| PRJNA991949 | ENA

C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions [GRID-Seq]

Project description:C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions [GRID-Seq]

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C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions [ChIP-Seq]

Project description:C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions [ChIP-Seq]

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C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions [RNA-Seq]

Project description:The hematopoietic master regulator RUNX1 is frequently mutated in myeloid and lymphoid malignancies. Analyses of RUNX1 mutations across hematopoietic tissues revealed frequent mutations outside of the N-terminal DNA binding domain. The vast majority of these C-terminal mutations were found to be nonsense and frameshifts resulting in truncated protein products predicted to escape nonsense mediated decay pathways. We modeled this class of truncation mutation using the pathogenic RUNX1 R320* mutation found in both germline and sporadic hematological disease. Homozygous knock-in of RUNX1 R320* in K562 leukemia cells resulted in a megakaryocytic differentiation block and DNA damage sensitivity phenotypes. Gene expression analysis demonstrated that RUNX1 R320* dysregulated unique gene sets when compared to RUNX1 knockdown in addition to shared genes related to megakaryocyte and platelet function. DNA binding across the genome was examined between RUNX1 wild-type and RUNX1 R320* through ChIP-seq, revealing that RUNX1 R320* differential binding was most enriched at enhancer regions. To detect RUNX1 R320* dysregulated enhancer-promoter (E-P) connections we performed GRID-seq and uncovered extensive remodeling of E-P interactions genome-wide in RUNX1 R320* cells. Furthermore, we uncovered a novel role for FOXK2 at RUNX1 regulated enhancers. Analysis of the well-studied MYC enhancer region demonstrated cooperation between RUNX1 R320* and FOXK2 at hematopoietic MYC enhancers NDME and BENC resulting in the significant upregulation of the MYC oncogene. In conclusion, the truncation of RUNX1 results in impaired megakaryocytic differentiation, unique transcriptional alterations, and remodeling of enhancer-promoter connections in cooperation with FOXK2, together contributing to leukemogenesis.

2024-05-29 | GSE236641 | GEO

C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions [GRID-Seq]

2024-05-29 | GSE236640 | GEO

C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions [ChIP-Seq]

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RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program

Project description:RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program

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C-terminal Mutations in RUNX1 Induce Differentiation Block and Alter Transcription through Changes in Enhancer-Promoter Interactions

Project description:This SuperSeries is composed of the SubSeries listed below.

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Gene expression signatures of C-terminal shorter RUNX1 protein hematopoietic models

Project description:RUNX1 gene chromosomal translocations and mutations are frequent in acute myeloid leukaemia, sometimes resulting in the aberrant expression of C-terminal-truncated RUNX1 proteins lacking the transactivation domain (TAD). Some AML patients anomalously over-express a RUNX1a splice variant with the same TAD deficit. We performed an in-depth in vitro study of the role of TAD-defective RUNX1 proteins in AML development in human hematopoietic/progenitor stem cells. Transformation ability, maturation phenotype and differentiation/proliferation effects were assessed. Short RUNX1 protein expression seemed to increase both proliferation and self-renewal capacity, disrupting the differentiation program and interfering with wild-type RUNX1b protein, in a dominant-negative, dose-dependent manner. Expression microarray analysis showed short RUNX1 and RUNX1/ETO models had similar aberrant expression patterns. Genes known to be broadly involved in self-renewal and leukemogenesis were found to be altered; specifically observed were overexpression of homeobox genes, downregulation of primitive erythroid genes and alterations in leukemogenic transcription factors. The Wnt/b-catenin and RhoA pathways were also observed to be altered, whereas short RUNX1 proteins appeared not to affect the Notch1 pathway, which is altered in the RUNX1/ETO model. Therefore, we propose that TAD-defective RUNX1 proteins may contribute to leukemogenesis and could form the basis of a new genetic category of AML. Comparative experiment: Human CD34+ hematopoietic cells gene expression was measured after TAD defective RUNX1 cDNA transfection vs empty vector transfection. Two independent experiments were performed for each protein model, using different cord blood donors for each experiment.

2014-01-01 | E-GEOD-48523 | biostudies-arrayexpress

RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program (RNA-Seq)

Project description:RUNX1 mutations lead to a myeloid differentiation block by altering the RUNX1 transcriptional program (RNA-Seq)

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