EKLF/Klf1 regulates erythroid transcription by its pioneering activity and selective control of RNA Pol II pause-release
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ABSTRACT:
PROVIDER: PRJNA867412 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20968815.fastq.gz | Fastqsanger.gz | |||
| SRR20968816.fastq.gz | Fastqsanger.gz | |||
| SRR20968817.fastq.gz | Fastqsanger.gz | |||
| SRR20968818.fastq.gz | Fastqsanger.gz | |||
| SRR20968819.fastq.gz | Fastqsanger.gz |
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Project description:EKLF/Klf1 is a Zinc-finger transcription activator essential for erythroid lineage commitment and terminal differentiation. Using ChIP-Seq, we investigate EKLF DNA binding and transcription activation mechanisms during mouse embryonic erythropoiesis. Our study focuses on global EKLF binding dynamics during embryonic erythropoiesis in primary WT and Nan/+ mouse fetal liver, and its correlation with chromatin accessibility, CBP occupancy, histone acetylation, and finally its effect on RNA Polymerase II pausing and elongation. Our goal is to elucidate the mechanisms of transcription activation by EKLF/Klf1 during embryonic erythropoiesis in vivo and in the context of RNA pol II pause-release control. Additionally, we aim to understand the unusually severe effects of conservative E to D change in Nan-EKLF and the molecular mechanisms leading to dominant anemia through global gene dysregulation.
2023-01-18 | GSE210779 | GEO
Project description:EKLF/Klf1 is a zinc-finger transcription activator essential for erythroid lineage commitment and terminal differentiation. Using ChIP-seq, we investigate EKLF DNA binding and transcription activation mechanisms during mouse embryonic erythropoiesis. We utilize the Nan/+ mouse that expresses the EKLF-E339D (Nan) variant mutated in its conserved zinc-finger region and address the mechanism of hypomorphic and neomorphic changes in downstream gene expression. First, we show that Nan-EKLF limits normal EKLF binding to a subset of its sites. Second, we find that ectopic binding of Nan-EKLF occurs largely at enhancers and activates transcription through pioneering activity. Third, we find that for a subset of ectopic targets, gene activation is achieved in Nan/+ only by Nan-EKLF binding to distal enhancers, leading to RNA polymerase II pause-release. These results have general applicability to understanding how a DNA binding variant factor confers dominant disruptive effects on downstream gene expression even in the presence of its normal counterpart.
| S-EPMC9879271 | biostudies-literature
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: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.
2010-04-08 | GSE20478 | GEO
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:We describe a case of severe neonatal anemia with kernicterus due to compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1 null human. The phenotype of severe DAT-negative non-spherocytic hemolytic anaemia (NSHA), jaundice, hepato-splenomegaly, and marked erythroblastosis is more severe than that present in CDA type IV due to dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis. mRNA sequencing on peripheral blood from a family trio (mother, father and proband) where parents were asymptomatic and proband had severe neonatal anemia.
2015-01-01 | E-GEOD-60514 | biostudies-arrayexpress
Project description:Distal enhancers characterized by H3K4me1 mark play critical roles in developmental and transcriptional programs. However, potential roles of specific distal regulatory elements in regulating RNA Polymerase II (Pol II) promoter-proximal pause release remain poorly investigated. Here we report that a unique cohort of jumonji C domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) co-bound distal enhancers, termed anti-pause enhancers (A-PEs), regulate promoter-proximal pause release of a large subset of transcription units via long-range interactions. Brd4-dependent JMJD6 recruitment on A-PEs mediates erasure of H4R3me2(s), which is directly read by 7SK snRNA, and decapping/demethylation of 7SK snRNA, ensuring the dismissal of the 7SKsnRNA/HEXIM inhibitory complex. The interactions of both JMJD6 and Brd4 with the P-TEFb complex permit its activation and pause release of regulated coding genes. The functions of JMJD6/ Brd4-associated dual histone and RNA demethylase activity on anti-pause enhancers have intriguing implications for these proteins in development, homeostasis and disease. All Gro-seq(s) were designed to reveal the transcriptional targets of JMJD6 and Brd4, and assess the role of JMJD6 and Brd4 in Pol II promoter-proximal pause release. All ChIP-seq(s) were designed to understand the unique features, associated molecular mechanisms and functions of the anti-pause enhancers (A-PEs) discovered in the current study.
2014-01-14 | E-GEOD-51633 | biostudies-arrayexpress
Project description:We describe a case of severe neonatal anemia with kernicterus due to compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1 null human. The phenotype of severe DAT-negative non-spherocytic hemolytic anaemia (NSHA), jaundice, hepato-splenomegaly, and marked erythroblastosis is more severe than that present in CDA type IV due to dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis.
2015-01-01 | GSE60514 | GEO
Project description:The onset of erythropoiesis is under strict developmental control, with direct and indirect inputs influencing its derivation from the hematopoietic stem cell. A major regulator of this transition is KLF1/EKLF, a zinc finger transcription factor that plays a global role in all aspects of erythropoiesis. Here, we have identified a short, conserved enhancer element in KLF1 intron 1 that is important for establishing optimal levels of KLF1 in mouse and human cells. Chromatin accessibility of this site exhibits cell-type specificity and is under developmental control during the differentiation of human CD34+ cells towards the erythroid lineage. This site binds GATA1, SMAD1, TAL1, and ETV6. In vivo editing of this region in cell lines and primary cells reduces KLF1 expression quantitatively. However, we find that, similar to observations seen in pedigrees of families with KLF1 mutations, downstream effects are variable, suggesting that the global architecture of the site is buffered towards keeping the KLF1 genetic region in an active state. We propose that modification of intron 1 in both alleles is not equivalent to complete loss of function of one allele.
2023-08-04 | GSE223212 | GEO