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Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE142228 | GEO | 2020/08/25

REPOSITORIES: GEO

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Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin organization.

Project description:The underlying mechanism of transcriptional co-repressor ETO2 during early erythropoiesis and hemoglobin switching is unclear. We find that absence of ETO2 in mice interferes with down-regulation of PU.1 and GATA2 in the fetal liver, impeding a key step required for commitment to erythroid maturation. In human β-globin transgenic Eto2 null mice and in human CD34+ erythroid progenitor cells with reduced ETO2, loss of ETO2 results in ineffective silencing of embryonic/fetal globin gene expression, impeding hemoglobin switching during erythroid differentiation. ETO2 occupancy genome-wide occurs virtually exclusively at LDB1-complex binding sites in enhancers and ETO2 loss leads to increased enhancer activity and expression of target genes. ETO2 recruits the NuRD nucleosome remodeling and deacetylation complex to regulate histone acetylation and nucleosome occupancy in the β-globin locus control region and γ-globin gene. Loss of ETO2 elevates LDB1, MED1 and Pol II in the locus and facilitates fetal γ-globin/LCR looping and γ-globin transcription. Absence of the ETO2 hydrophobic heptad repeat region impairs ETO2-NuRD interaction and function in antagonizing γ-globin/LCR looping. Our results reveal a pivotal role for ETO2 in erythropoiesis and globin gene switching through its repressive role in the LDB1 complex, affecting the transcription factor and epigenetic environment and ultimately restructuring chromatin organization.

| S-EPMC7544236 | biostudies-literature

Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping (ChIP-Seq)

Project description:To determine direct targets and the regulatory role of ETO2 in gene expression, we performed ChIPmentation with antibodies to unmodified ETO2 and ETO2 interacted factor LDB1. A de novo MEME search performed on ETO2-occupied sites, revealed enrichment for GATA and TAL binding motifs, which are the components in LDB1 complex. Nearly 86% of ETO2-binding sites were intergenic or intronic, suggesting ETO2 functions primarily in regions of the genome likely to encompass enhancers. Notabley, ETO2 occupancy was almost completely coincident with LDB1 (97% of 7,761 sites), consistent with the presence of ETO2 exclusively within the LDB1 complex and their co-function in gene regulation.

2020-08-25 | GSE142227 | GEO

Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping (RNA-Seq)

Project description:ETO2 functions as a transcription repressor and is required for the embryonic erythropoiesis and the hemoglobin switch. To gain insight into ETO2 regulatory function during human erythropoiesis, we performed RNA-seq for WT and ETO2 KO K562 cells and found that up-regulated genes upon ETO2 loss in human cells included many markers of mature erythroid cells EPB42, ALAS2, GYPA and SLC25a37. Notably, the α-globin genes (HBA1, HBA2 and HBZ) and embryonic and fetal β-globin genes (HBE1, HBG1, and HBG2) were significantly increased after deletion of ETO2. By contrast, deletion of ETO2 down-regulated the transcription factor genes (ETS1, KLF8 and SOX6) which play a negative role in globin gene expression and hemoglobin synthesis. To further explore different domain function of ETO2, we have analyzed our RNA-seq data from domain deletion cell lines compared to the cell line expressing wild type ETO2. Generally, 702 genes were found to co-regulated by three domain function of ETO2. Interestingly, the regulation of fetal globin genes, erythroid regulator (SOX5) as well as epigenetic factor (HDAC7) is required by three domain function of ETO2. During mouse embryonic erythropoiesis, our FACS-sorted and normal RNA-seq data in E14.5 fetal liver cells indicated that eto2 promoted a critical developmental transition and played an important role in globin switch from embryonic to adult β-globin transcription since its function is essential for key regulators (PU.1, BCL11A and ZBTB7A) and globin genes (Hbb-y and Hba-x) regulation.

2020-08-25 | GSE142226 | GEO

Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping [RNA-Seq 2]

Project description:During the human cord blood CD34+ cell differentiation, expression of the genes which contribute to erycyte maturation are increased, inculding ALAS2, SLC25A37, GYPA and KLF1. ETO2 functions as a transcription repressor and is required for the erythrocyte maturation and the hemoglobin switch. During mouse embryonic erythropoiesis, RNA-seq data in E8.5 yolk sac /E12.5, E14.5 fetal liver cells indicated that eto2 promoted a critical developmental transition and played an important role in globin switch from embryonic to adult β-globin transcription since its function is essential for erythorid maturation regulators (Alas2,Slc25a37,Epb42,Gypc,Klf1) and globin genes (Hbb-y and Hba-x) regulation.

2020-08-25 | GSE156306 | GEO

Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping

Project description:Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping

| PRJNA596249 | ENA

Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping (RNA-Seq)

Project description:Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping (RNA-Seq)

| PRJNA596255 | ENA

Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping (ChIP-Seq)

Project description:Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping (ChIP-Seq)

| PRJNA596254 | ENA

Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping [RNA-Seq 2]

Project description:Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin accessibility and looping [RNA-Seq 2]

| PRJNA657407 | ENA

ETO2 coordinates cellular proliferation and differentiation during erythropoiesis.

Project description:The passage from proliferation to terminal differentiation is critical for normal development and is often perturbed in malignancies. To define the molecular mechanisms that govern this process during erythropoiesis, we have used tagging/proteomics approaches and characterized protein complexes nucleated by TAL-1/SCL, a basic helix-loop-helix transcription factor that specifies the erythrocytic lineage. In addition to known TAL-1 partners, GATA-1, E2A, HEB, LMO2 and Ldb1, we identify the ETO2 repressor as a novel component recruited to TAL-1 complexes through interaction with E2A/HEB. Ectopic expression and siRNA knockdown experiments in hematopoietic progenitor cells show that ETO2 actively represses erythroid TAL-1 target genes and governs the expansion of erythroid progenitors. At the onset of erythroid differentiation, a change in the stoichiometry of ETO2 within the TAL-1 complex activates the expression of known erythroid-specific TAL-1 target genes and of Gfi-1b and p21(Cip), encoding two essential regulators of erythroid cell proliferation. These results suggest that the dynamics of ETO2 recruitment within nuclear complexes couple cell proliferation to cell differentiation and determine the onset of terminal erythroid maturation.

| S-EPMC1383517 | biostudies-literature

Erythroid lineage chromatin accessibility maps facilitate identification and validation of NFIX as a fetal hemoglobin repressor.

Project description:Human genetics has validated de-repression of fetal gamma globin (HBG) in adult erythroblasts as a powerful therapeutic paradigm in diseases involving defective adult beta globin (HBB)1. To identify factors involved in the switch from HBG to HBB expression, we performed Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq)2 on sorted erythroid lineage cells derived from bone marrow (BM) or cord blood (CB), representing adult and fetal states, respectively. BM to CB cell ATAC-seq profile comparisons revealed genome-wide enrichment of NFI DNA binding motifs and increased NFIX promoter chromatin accessibility, suggesting that NFIX may repress HBG. NFIX knockdown in BM cells increased HBG mRNA and fetal hemoglobin (HbF) protein levels, coincident with increased chromatin accessibility and decreased DNA methylation at the HBG promoter. Conversely, overexpression of NFIX in CB cells reduced HbF levels. Identification and validation of NFIX as a new target for HbF activation has implications in the development of therapeutics for hemoglobinopathies.

| S-EPMC10267139 | biostudies-literature

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