Transcriptional activation of the PKLR gene by novel erythroid-specific regulatory elements [ChIP-Seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE295819 | GEO | 2026/04/25
REPOSITORIES: GEO
Similar Datasets
Project description:Transcriptional activation of the PKLR gene by novel erythroid-specific regulatory elements [ChIP-Seq]
| PRJNA1256435 | ENA
Project description:Background & Aims Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver pathologies. However, not medical treatment has been approved for the disease so far. In our previous study, we found PKLR could be a potential target for treatment of NALFD. Here the aim is to investigate the effect of PKLR in in vivo model and reposition a drug which could be used for treatment of NAFLD. Results The Pklr KO reversed the increased hepatic triglyceride level in mice fed with high sucrose diet and partly recovered the transcriptomic changes in liver as well as other three tissues. Both liver and white adipose tissues exhibited dysregulated circadian transcriptomic profiles, and these dysregulations were reversed by hepatic knockout of Pklr. In addition, 10 small molecule drugs were identified as potential inhibitor of PKLR by the drug repositioning pipeline, and two of them significantly inhibited both the PKLR expression and triglyceride level in in vitro model. Finally, the two selected small molecule drugs were evaluated in in vivo rat models and it was demonstrated that these drugs attenuated hepatic steatosis without side effect on other tissues. Conclusion: In conclusion, our study provided biological insights about the critical role of PKLR in NAFLD progression and proposed a treatment strategy for NAFLD patients, which could be validated in further clinical trials.
2022-07-22 | GSE193627 | GEO
Project description:Erythroid enucleation is the final stage of erythroid terminal differentiation and involves the separation of an orthochromatic erythroblast into two daughter cells; a pyrenocyte containing the extruded nucleus, and a reticulocyte that will become a red blood cell. Our previous work identified CDK9 as a regulator of erythroid enucleation that appears to act independently of its known role in regulating RNA polymerase II transcription, suggesting the potential for a new CDK9 role. Using a co-immunoprecipitation and mass spectrometry approach, we identified the interactome of CDK9 in differentiating erythroblasts. We show that CDK9 interacts with a RanGTP-NEMP1-Importin-β complex during erythroid terminal differentiation, and inhibition of importin-β in erythroblasts blocks erythroid enucleation. Using imaging analysis and functional assays of enucleating erythroblasts, we show that CDK9 and importin-β co-locate at a critical site of activity opposite to the nucleus before nuclear extrusion and we describe a novel finding that physically links CDK9 and importin-β activity prior to CaM/Ca2+ signalling and subsequent F-actin activity to achieve enucleation.
2026-04-01 | PXD072077 | Pride
Project description:Gene expression during cellular differentiation is coordinated by combinatorial interactions between transcription factors (TFs) and cofactors at promoters and enhancers. The “master TF” GATA1 coordinates gene transcription in a subset of hematopoietic lineages, including erythroid, megakaryocytic, mast, and eosinophil, while repressing the development of other blood lineages. However, the specific cofactors required for GATA1-activated gene expression during hematopoiesis are incompletely defined. We identified the cofactor KMT2D, an H3K4 methyltransferase that collaborates with H3K27 acetyltransferases to activate transcription, in an unbiased CRISPR/Cas9 screen for epigenetic regulators of erythropoiesis. Loss of KMT2D in human erythroid precursors caused developmental arrest with impaired expression of numerous erythroid genes. Mechanistically, KMT2D colocalized with GATA1 on more than one thousand erythroid enhancers associated with over two hundred erythroid genes. In general, co-occupancy of GATA1 and KMT2D at erythroid enhancers was associated with stronger transcriptional activity than occupancy by GATA1 alone. Acute depletion of KMT2D in erythroid precursors caused rapid reductions of H3K4me1 and H3K27ac on a subset of GATA1-bound enhancers and impaired the expression of canonical erythroid genes, including ZFPM1, SLC4A1, and EPOR. Moreover, acute depletion of GATA1 or KMT2D individually caused downregulation of overlapping gene sets. Thus, KMT2D controls erythropoiesis by selectively activating GATA1-dependent erythroid enhancers. Our studies identify KMT2D as a novel cofactor for transcriptional activation by GATA1 during erythropoiesis. More generally, our findings demonstrate how a lineage-specific TF cooperates with a ubiquitous epigenetic regulator to drive lineage-specific gene expression during cellular differentiation.
2026-04-10 | PXD076443 | Pride
Project description:Impact on erythroid progenitor type on erythroid differntiation
| PRJNA515507 | ENA
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.
2012-04-01 | GSE33979 | GEO
Project description:Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning
| PRJNA796970 | ENA
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