The landscape of global long-range interactions in human erythroid cells mediated by GATA1 and CTCF during differentiation
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PROVIDER: PRJNA433533 | ENA |
REPOSITORIES: ENA
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Project description:A network of long-range interactions between functional DNA elements regulates gene expression in a precise spatio-temporal pattern during development. We carried out anti-RNA polymerase II and cohesin ChIA-PET and DNase-seq in Mouse Erythroleukemia (MEL) cells to capture genome-wide changes between open chromatin elements in chromatin interaction graphs (CIGs) during DMSO-induced hemoglobin activation. We found that the change of interaction strength in CIGs is positively correlated to expression changes in corresponding genes as measured by RNA-seq. DNaseI footprints and ChIP-seq data indicate that these long-range interactions are controlled through distinct combinations of transcription factors before and after differentiation, with CTCF or cohesin only mediating half of these interactions, with GATA1, PU.1 and/or other transcription factorsYY1 interactions accounting for an additional 40% of detected interactions. Strikingly, while CTCF and GATA1–mediated interactions were enriched in genes involved in erythrocyte differentiation and mitochondrial regulation, PU.1YY1-mediated interactions were enriched for genes involved in RNA processing, cell cycletranslation, and chromatin organizationhistone remodeling. We further found that two-thirds of MEL DNA elements with long-range interactions as well as 35% of their interactions are conserved in human K562 cells and they show similar combinations of factor occupancy in both species. Our study highlights the importance of quantitative analysis of changes in long-range interaction strengths in quantifying changes in gene expression.
2020-02-29 | GSE110361 | GEO
Project description:Abstract: A network of interactions between functional DNA elements regulates gene expression in a precise spatio-temporal pattern during development. This regulation is implemented through many-to-many looping interactions of DNA elements mediated by specific transcription factors such as Ctcf, Gata1 and Yy1. We carried out RNA polymerase II ChIA-PET and DNase-seq in Mouse Erythroleukemia (MEL) cells to capture genomewide changes in the resulting chromatin interaction graphs (CIGs) during DMSO-induced hemoglobin activation. We found that the change of interactions in CIGs is positively correlated to the change of a corresponding genes’ expression as measured by RNA-seq. DNase footprints and ChIP-seq data indicate that these long-range interactions are controlled through distinct combinations of transcription factors before and after differentiation, with Ctcf or cohesin only mediating half of these interactions, and Gata1 and/or Yy1 interactions accounting for an additional 40% of detected interactions. Strikingly, while Ctcf and Gata1–mediated interactions were enriched in genes involved in erythrocyte differentiation and mitochondrial regulation, Yy1-mediated interactions were enriched for genes involved in RNA processing, translation, and histone remodeling. We further found that about two-thirds of MEL DNA elements with long-range interactions as well 35% of these interactions are conserved in human K562 cells and show similar combinations of factor occupancy. Taken together, our study identifies that a large set of long-range interactions between active enhancers and promoters involving RNA Pol II are mediated by factors other than cohesin and Ctcf in both human and mouse.
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Project description:RP-LC-MS lipidomics data was collected to understand the role of GATA1 during erythroid maturation. GATA1 mutants and WT cells were treated with or without beta-estradiol. GATA1 mutant cells were additionally treated with or without 5-ALA.
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Project description:Nuclear receptor binding SET domain protein 1 (NSD1) is recurrently mutated in human cancers including acute leukemia. We found that NSD1 knockdown altered erythroid clonogenic growth of human CD34+ hematopoietic cells. Ablation of Nsd1 in the hematopoietic system induced a transplantable erythroleukemia in mice. Despite abundant expression of the transcriptional master regulator GATA1, in vitro differentiation of Nsd1-/- erythroblasts was majorly impaired associated with reduced activation of GATA1-induced targets, while GATA1-repressed target genes were less affected. Retroviral expression of wildtype Nsd1, but not a catalytically-inactive Nsd1N1918Q SET-domain mutant induced terminal maturation of Nsd1-/- erythroblasts. Despite similar GATA1 levels, exogenous Nsd1 but not Nsd1N1918Q significantly increased GATA1 chromatin occupancy and target gene activation. Notably, Nsd1 expression reduced the association of GATA1 with the co-repressor SKI, and knockdown of SKI induced differentiation of Nsd1-/- erythroblasts. Collectively, we identified the NSD1 methyltransferase as a novel regulator of GATA1-controlled erythroid differentiation and leukemogenesis.
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2013-03-04 | E-GEOD-43356 | biostudies-arrayexpress
Project description:Missense mutations in transcription factor GATA1 underlie several distinct forms of anemia and thrombocytopenia. Clinical severity depends on the site and type of substitution, and distinct substiutions of the same residue produce disparate phenotypes. To investigate the effect of GATA1 missense mutations on erythroid differentiation we expressed conditionally activated wild type or mutant versions of GATA1 in GATA1-null G1E cells. We used gene expression microarrays to explore how GATA1 missense mutations affect erythroid transcription programs.
2013-03-04 | GSE43356 | GEO
Project description:In mice lacking the heme exporter, FLVCR, differentiation fails at the CFU-E/proerythroblast stage from excessive heme and reactive oxygen species. We show that Flvcr1-deleted CFU-E/proerythroblasts have low GATA1 mRNA and GATA1-target gene mRNAs along with increased ribosomal protein mRNAs as a direct result of increased heme. Thus heme increases ribosomal protein transcription when globin production needs to be increased, and when heme is excessive, GATA1 is reduced allowing for normal termination of erythroid differentiation. This demonstrates that heme and GATA1 are co-master regulators of erythroid differentiation.
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Project description:In mice lacking the heme exporter, FLVCR, differentiation fails at the CFU-E/proerythroblast stage from excessive heme and reactive oxygen species. We show that Flvcr1-deleted CFU-E/proerythroblasts have low GATA1 mRNA and GATA1-target gene mRNAs along with increased ribosomal protein mRNAs as a direct result of increased heme. Thus heme increases ribosomal protein transcription when globin production needs to be increased, and when heme is excessive, GATA1 is reduced allowing for normal termination of erythroid differentiation. This demonstrates that heme and GATA1 are co-master regulators of erythroid differentiation.
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Project description:We report the occupancy of GATA1 and TAL1, two erythroid transcription factors, and H3K27ac histone modification in human erythroid precursors.
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