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CTCF is selectively required for maintaining chromatin accessibility and gene expression in human erythropoiesis [ChIP-seq_GATA1]

ABSTRACT: By using an unbiased genetic screen and proteome profiling in human erythroblast, we identified and verified KMT2D as an essential factor for human erythropoiesis. Accordingly, we observed that KMT2D is indispensable for the activation of erythroid signature genes in a stage dependent manner. Moreover, to further study the direct transcriptional regulatory role of KMT2D, we established two endogenous N-terminus AID-KMT2D system in t human erythroblast cell lines and systematically investigated the effects of acute KMT2D loss by auxin-inducible degron system on transcriptional programs and chromatin accessibility. By integrating multi-omics datasets, we revealed that acute KMT2D loss notably suppressed the subset of GATA1 downstream targets. Importantly, we profiled the specific genome-wide occupancy of KMT2D by comparison between the presence and absence of KMT2D in AID model. Strikingly, KMT2D occupies over hundreds of erythroid specific genes mostly on their promoters. More importantly, we revealed that the KMT2D co-localized with GATA1 in numerous erythroid genes and the occupancy of GATA1 significantly reduced after KMT2D degradation. These results suggest KMT2D is indispensable for the enhancer-binding of GATA1 in gene expression in erythroid lineage specification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281735 | GEO | 2025/01/27

REPOSITORIES: GEO

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Inactivation of the nuclear interacting SET domain protein 1 (NSD1) impairs GATA1-regulated erythroid differentiation and causes erythroleukemia

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.

2020-04-08 | PXD017657 | Pride

CTCF is selectively required for maintaining chromatin accessibility and gene expression in human erythropoiesis [ChIP-seq_CTCF]

Project description:The three-dimensional chromatin niche provides a precise gene expression control of cell identity, differentiation, and disease development. CTCF is considered as the most essential transcription factor regulating chromatin architecture and gene expression. However, the genome-wide impact of CTCF in erythropoiesis has not been extensively investigated yet. To further study the direct transcriptional regulatory role of CTCF, we established two endogenous C-terminus AID-CTCF system in t human erythroblast cell lines and systematically investigated the effects of acute CTCF loss by auxin-inducible degron system on transcriptional programs and chromatin accessibility. By integrating multi-omics datasets, we revealed that acute CTCF loss notably suppressed the subset of GATA1 downstream targets. Importantly, we revealed that acute CTCF loss notably disrupted genome-wide chromatin accessibility and transcription network. Importantly, we identified that over thousands of chromatin accessibility regions were decreased while only a few hundreds of increased regions after depletion of CTCF in both HUDEP-2 and HEL lines, suggesting the role of CTCF in maintaining the proper chromatin openness in erythroid lineage. Moreover, CTCF depletion in erythroid context significantly disrupted TAD boundary integrity and chromatin loops while not affecting the nuclear compartmentalization. In summary, our results addressed a novel role of CTCF in regulating erythroid differentiation by maintaining its proper chromatin openness, which will undoubtedly extend our understanding of CTCF biology.

2025-01-27 | GSE281734 | GEO

CTCF is selectively required for maintaining chromatin accessibility and gene expression in human erythropoiesis [RNA-seq]

2025-01-27 | GSE281733 | GEO

Genome-wide maps of GATA1, TAL1, and H3K27ac occupancy in erythroid precursors

Project description:We report the occupancy of GATA1 and TAL1, two erythroid transcription factors, and H3K27ac histone modification in human erythroid precursors.

2017-01-10 | GSE93372 | GEO

Erythroid differentiation: G1E model

2009-09-10 | GSE18042 | GEO

Genome-wide ChIP-Seq reveals a dramatic shift in the binding of the transcription factor erythroid Kruppel-like factor during erythrocyte differentiation

Project description:Erythropoiesis is dependent on the activity of transcription factors, including the erythroid-specific erythroid Kruppel-like factor (EKLF). ChIP followed by massively parallel sequencing (ChIP-Seq) is a powerful, unbiased method to map transfactor occupancy. We used ChIP-Seq to study the interactome of EKLF in mouse erythroid progenitor cells and more differentiated erythroblasts. We correlated these results with the nuclear distribution of EKLF, RNA-Seq analysis of the transcriptome, and the occupancy of other erythroid transcription factors. In progenitor cells, EKLF is found predominantly at the periphery of the nucleus, where EKLF primarily occupies the promoter regions of genes and acts as a transcriptional activator. In erythroblasts, EKLF is distributed throughout the nucleus, and erythroblast-specific EKLF occupancy is predominantly in intragenic regions. In progenitor cells, EKLF modulates general cell growth and cell cycle regulatory pathways, whereas in erythroblasts EKLF is associated with repression of these pathways. The EKLF interactome shows very little overlap with the interactomes of GATA1, GATA2, or TAL1, leading to a model in which EKLF directs programs that are independent of those regulated by the GATA factors or TAL1. (Blood.2011;118(17):e139-e148) We used ChIP-Seq to study the interactome of EKLF in mouse erythroid progenitor cells and more differentiated erythroblasts and RNA-Seq analysis of the transcriptome.

2013-06-17 | E-GEOD-48020 | biostudies-arrayexpress

Pluripotent stem cells reveal novel erythroid activities of the GATA1 N-terminus

Project description:This SuperSeries is composed of the SubSeries listed below. Germline GATA1 mutations resulting in the production of an amino-truncated protein termed GATA1s (for M-bM-^@M-^\shortM-bM-^@M-^]) cause congenital hypoplastic anemia. Similar somatic mutations promote transient myeloproliferative disease and acute megakaryoblastic leukemia in trisomy 21 patients. Here we show that induced pluripotent stem cells (iPSCs) from patients with GATA1-truncating mutations exhibit impaired erythroid potential but enhanced megakaryopoiesis and myelopoiesis, faithfully recapitulating the major phenotypes of associated diseases. Similarly, GATA1s promotes megakaryopoiesis but not erythropoiesis in developmentally arrested Gata1- murine megakaryocyte-erythroid progenitors derived from murine embryonic stem cells (ESCs). Transcriptome studies demonstrate a selective deficiency in the ability of GATA1s to activate erythroid-expressed genes within populations of hematopoietic progenitors. Although its DNA binding domain is intact, chromatin immunoprecipitation studies show that GATA1s binding at specific erythroid regulatory regions is impaired, while binding at many non-erythroid sites, including megakaryocytic and myeloid target genes, is normal. These observations point to lineage specific GATA1 co-factor associations essential for normal chromatin occupancy and provide mechanistic insights into how GATA1s mutations cause human disease. More broadly, our studies underscore the value of ESCs and iPSCs to recapitulate and study disease phenotypes. Refer to individual Series

2015-01-26 | E-GEOD-61933 | biostudies-arrayexpress

Pluripotent stem cells reveal novel erythroid activities of the GATA1 N-terminus

Project description:This SuperSeries is composed of the SubSeries listed below. Germline GATA1 mutations resulting in the production of an amino-truncated protein termed GATA1s (for “short”) cause congenital hypoplastic anemia. Similar somatic mutations promote transient myeloproliferative disease and acute megakaryoblastic leukemia in trisomy 21 patients. Here we show that induced pluripotent stem cells (iPSCs) from patients with GATA1-truncating mutations exhibit impaired erythroid potential but enhanced megakaryopoiesis and myelopoiesis, faithfully recapitulating the major phenotypes of associated diseases. Similarly, GATA1s promotes megakaryopoiesis but not erythropoiesis in developmentally arrested Gata1- murine megakaryocyte-erythroid progenitors derived from murine embryonic stem cells (ESCs). Transcriptome studies demonstrate a selective deficiency in the ability of GATA1s to activate erythroid-expressed genes within populations of hematopoietic progenitors. Although its DNA binding domain is intact, chromatin immunoprecipitation studies show that GATA1s binding at specific erythroid regulatory regions is impaired, while binding at many non-erythroid sites, including megakaryocytic and myeloid target genes, is normal. These observations point to lineage specific GATA1 co-factor associations essential for normal chromatin occupancy and provide mechanistic insights into how GATA1s mutations cause human disease. More broadly, our studies underscore the value of ESCs and iPSCs to recapitulate and study disease phenotypes.

2015-01-26 | GSE61933 | GEO

Genome-wide ChIP-Seq reveals a dramatic shift in the binding of the transcription factor erythroid Kruppel-like factor during erythrocyte differentiation

2013-06-17 | GSE48020 | GEO

Transcription profiling of mouse erythroid differentiation using Gata1 gene-disrupted G1E ER4 clone cells

Project description:Analysis of erythroid differentiation using Gata1 gene-disrupted G1E ER4 clone cells. Estradiol addition activates an ectopically expressed Gata-1-estrogen receptor fusion protein, triggering synchronous differentiation. 30 hour time course corresponds roughly to late burst-forming unit-erythroid stage (t=0 hrs) through orthochromatic erythroblast stage (t=30 hrs). Experiment Overall Design: G1E ER4 cells cultured in G1E medium were treated at 6 time points with estradiol to initiate erythroid differentiation by activating Gata1 transcription factor and total RNAs from treated cells were extracted for microarray experiment. The erythroid differentiation status was confirmed by cell pellet color and expression of microRNA miR451. The design was similar to an earlier studies (Welch, J. J., Watts, J. A., Vakoc, C. R., Yao, Y., Wang, H., Hardison, R. C., Blobel, G. A., Chodosh, L. A., and Weiss, M. J. (2004)). Global regulation of erythroid gene expression by transcription factor GATA-1. Blood 104, 3136-3147), except that a more recent version of Affymetric chip was used to acheive greater transcriptome coverage.

2009-09-18 | E-GEOD-18042 | biostudies-arrayexpress

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