RNA-sequencing comparing activation of wild-type transcription factor KLF1 with mutant KLF1 (KLF1-325K) in iPSC-derived macrophages.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA950312 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24015418_1.fastq.gz | Fastqsanger.gz | |||
| SRR24015418_2.fastq.gz | Fastqsanger.gz | |||
| SRR24015419_1.fastq.gz | Fastqsanger.gz | |||
| SRR24015419_2.fastq.gz | Fastqsanger.gz | |||
| SRR24015420_1.fastq.gz | Fastqsanger.gz |
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Project description:Congenital dyserythropoietic anaemia (CDA) type IV has been associated with an amino acid substitution, Glu325Lys (E325K), in the transcription factor KLF1. Patients with CDA type IV present with a range of symptoms, including the persistence of nucleated red blood cells (RBCs) in the peripheral blood which reflects the known role for KLF1 within the erythroid cell lineage. The final stages of RBCs maturation and enucleation take place within the erythroblastic island (EBI) niche in close association with EBI macrophages. It is not known whether the detrimental effects of the E325K mutation in KLF1 are restricted to the erythroid lineage or whether deficiencies in macrophages associated with their niche also contribute to the disease pathology. To address this question, we generated iPSC lines genetically modified to express a KLF1-E325K-ERT2 protein that could be activated with 4OH-tamoxifen. We performed bulk RNA-sequencing on macrophages generated from these iPSCs, macrophages generated from one KLF1-E325K-ERT2 iPSC line (iCDA4.1) was compared to macrophages generated from one inducible KLF1-WT-ERT2 (K2) iPSC line which was derived from the same parental iPSCs (SFCi55) as the KLF1-E325K-ERT2 line.
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Project description:In this project we did a proteomic analysis from iPSCs-derived macrophages with the activation of thranscription factor KLF1, upon tamoxifen induction. These macrophages are a model for the study of the erythroid island (EI) niche in adult hematopoietic tissues, such as bone marrow and spleen. We wanted to assess the upregulated proteins in macrophages upon KLF1 activation to further study the interactions between macrophages and erythroid cells whithin the EI niche.
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Project description:Red blood cells (RBCs) mature within a specialized niche (the erythroblastic island (EI)), which consists of a central macrophage surrounded by differentiating erythroblasts. Human Induced Pluripotent Stem Cell derived macrophages (iPSC-DMs) enhance proliferation and terminal maturation of Umbilical Cord Blood (UCB) CD34+ derived erythroid cells and iPSC derived erythroid cells. These effects are further increased when an inducible KLF1-ERT2 fusion protein is activated in iPSC-DMs. To assess the mechanism of action, we sought to compare the transcriptome of iPSC-DMs with and without KLF1 activation. For this, we used an inducible IPSC line (iKLF1.2) in which upon tamoxifen addition, the KLF1 transcription factor is translocated to nucleus and consequently KLF1 downstream targets are expressed. The identification and characterisation of could identify factors involved in erythroid maturation and thus helpful to improve current protocols to manufacture RBCs in vitro.
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Project description:Klf1 (formerly known as Eklf) regulates the development of erythroid cells from bi-potent progenitor cells via the transcriptional activation of a diverse set of genes. Mice lacking Klf1 die in utero prior to E15 from severe anemia due to the inadequate expression of genes controlling hemoglobin production, cell membrane and cytoskeletal integrity, and the cell cycle and proliferation. We have recently described the full repertoire of Klf1 binding sites in vivo by performing Klf1 ChIP-seq in primary erythroid tissue (E14.5 fetal liver). Here we describe the Klf1-dependent erythroid transcriptome by comparing mRNA-seq from Klf1+/+ and Klf1-/- erythroid tissue. This has revealed novel target genes not previously obtainable by traditional microarray technology and provided novel insights into the function of Klf1 as a transcriptional activator such as interactions with Gata1, Scl/Tal1 and p300. We also describe a set of erythroid specific promoters not previously identified that drive high level expression of otherwise ubiquitously expressed genes in erythroid cells. Additionally, our study has identified for the first time two novel lnc-RNAs that are dynamically expressed during erythroid differentiation as well as a role for Klf1 in directing apoptotic gene expression to drive the terminal stages of erythroid maturation. Examination of mRNA expression in 3 Klf1-/- and 3 Klf1+/+ fetal livers This submission represents mRNA-Seq component of study.
2012-04-01 | E-GEOD-33979 | biostudies-arrayexpress
Project description:Klf1 (formerly known as Eklf) regulates the development of erythroid cells from bi-potent progenitor cells via the transcriptional activation of a diverse set of genes. Mice lacking Klf1 die in utero prior to E15 from severe anemia due to the inadequate expression of genes controlling hemoglobin production, cell membrane and cytoskeletal integrity, and the cell cycle and proliferation. We have recently described the full repertoire of Klf1 binding sites in vivo by performing Klf1 ChIP-seq in primary erythroid tissue (E14.5 fetal liver). Here we describe the Klf1-dependent erythroid transcriptome by comparing mRNA-seq from Klf1+/+ and Klf1-/- erythroid tissue. This has revealed novel target genes not previously obtainable by traditional microarray technology and provided novel insights into the function of Klf1 as a transcriptional activator such as interactions with Gata1, Scl/Tal1 and p300. We also describe a set of erythroid specific promoters not previously identified that drive high level expression of otherwise ubiquitously expressed genes in erythroid cells. Additionally, our study has identified for the first time two novel lnc-RNAs that are dynamically expressed during erythroid differentiation as well as a role for Klf1 in directing apoptotic gene expression to drive the terminal stages of erythroid maturation.
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Project description:Extracellular vesicles derived from induced pluripotent stem cells (iPSC EVs) have immunoregulatory potential with the ability to alter monocyte-derived macrophages. Macrophages function in the propagation and resolution of inflammation which is mediated by their phenotype. Macrophages are an ideal therapeutic target as modulating their phenotype towards an anti-inflammatory pro-resolving state may be beneficial in chronic inflammatory diseases such as atherosclerosis. Macrophages are naturally phagocytotic cells and readily take up iPSC EVs however the contents of iPSC EVs and their effects on macrophages are poorly understood. Here iPSC EVs were characterized and analysed by mass-spectrometry based proteomics and a targeted microRNA (miR) panel. Their immunomodulatory effects on macrophages were assessed and a monocyte transmigration assay was used to assess the chemotactic potency of the secretome from iPSC EV treated macrophages. Proteomic analysis on iPSC EVs identified Podocalyxin-like protein 1 (PODXL1), Insulin (INS) and Solute Carrier Family 2 (Facilitated Glucose Transporter), Member 3 (SLC2A3) as the most abundant proteins unique to the iPSC EVs when compared to control NT-2 EVs. Notably, thioredoxin and peroxiredoxin related proteins were detected. miR-302d-3p was the most abundant miR in these iPSC EVs. miR-25-3p, previously reported to alter the macrophage phenotype, was significantly increased in comparison to the control NT-2 EVs. iPSC EVs increased expression of the anti-inflammatory associated MRC1 and miR-21 in human primary macrophages and decreased monocyte chemoattractant protein1 (MCP-1). Mass spectrometry based proteomics revealed that treated macrophages had decreased levels of secretory proteins, some of which have chemotactic properties, these included Azurocidin 1 (AZU1), Growth Differentiation Factor 15 (GDF15), and Ribosomal Protein S19 (RPS19). There was a decrease in monocyte transmigration towards conditioned media from macrophages treated with iPSC EVs. Collectively this study provides insights into the protein content and miR cargo of iPSC EVs and highlights their capacity to inhibit chemotactic proteins in macrophages and upregulate MRC1.
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Project description:KLF1 (EKLF) regulates a diverse suite of genes to direct erythroid cell differentiation from bi-potent progenitors. To determine the local cis-regulatory contexts and transcription factor networks in which KLF1 operates, we performed KLF1 ChIP-seq in the mouse. We found at least 945 sites in the genome of E14.5 fetal liver erythroid cells which are occupied by endogenous KLF1. Many of these recovered sites reside in erythroid gene promoters such as β-globin, but the majority are distant to any known gene. Our data suggests KLF1 directly regulates most aspects of terminal erythroid differentiation including production of α and β-globin protein chains, heme biosynthesis, co-ordination of proliferation and anti-apoptotic pathways, and construction of the red cell membrane and cytoskeleton by functioning primarily as a transcriptional activator. Additionally, we suggest new mechanisms for KLF1 co-operation with other transcription factors, in particular the erythroid transcription factor GATA1, to maintain homeostasis in the erythroid compartment. Examination of KLF1 occupancy in primary erythroid cells. KLF1-ChIP and input samples were run on AB SOLiD Systems 2.0 and 3.0. The genomic alignment files (*sorted.txt) and peak file (*bed) contain the combined System 2.0 and 3.0 data.
2010-04-08 | E-GEOD-20478 | biostudies-arrayexpress
Project description:Fission yeast Schizosaccharomyces pombe is a model for studying cellular quiescence. Shifting to medium without a nitrogen-source induces proliferative cells to enter long-term G0 quiescence. Klf1 is a Kruppel-like transcription factor with a 7-amino acid-spaced C2H2-type zinc finger motif. The deletion mutant M-bM-^HM-^Fklf1 normally divides in vegetative medium, but proliferation is not restored after long-term G0 quiescence. Cell biologic, transcriptomic, and metabolomic analyses revealed a unique phenotype of the M-bM-^HM-^Fklf1 mutant in quiescence. Mutant cells had diminished transcripts related to signaling molecules for switching to differentiation. In contrast, proliferative metabolites for cell-wall assembly and antioxidants significantly increased. Further, the size of the M-bM-^HM-^Fklf1 cells is markedly increased during quiescence due to the aberrant accumulation of calcofluor-positive chitin-like materials beneath the cell wall. After 4 weeks quiescence, the ability for reversible proliferation is lost, but energy metabolism is maintained. Klf1 thus plays a role in G0 phase longevity through enhancing the differentiation signal and suppressing metabolism for growth. If Klf1 is lost, S. pombe fails to maintain a constant cell size during quiescence. Gene expression profile of fission yeast wild type cells and klf1-gene disruptant cells in proliferating state and in quiescent state. Type of experiment: Comparing between wild type cells and klf1-gene disruptant cells in proliferating condition and in quiescent condition. Experimental factor: Exponentially proliferating state in synthetic medium, EMM2, and quiescent G0 state in nitrogen-depleted synthetic medium, EMM2-N. Quality control steps taken: All experiments were repeated twice in each condition.
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