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Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient

ABSTRACT: Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient

PROVIDER: PRJNA528630 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8769790.fastq.gz	Fastqsanger.gz
	SRR8769800.fastq.gz	Fastqsanger.gz
	SRR8769810.fastq.gz	Fastqsanger.gz
	SRR8769820.fastq.gz	Fastqsanger.gz
	SRR8769830.fastq.gz	Fastqsanger.gz

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Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient

Project description:Congenital dyserythropoietic anemia (CDA) type IV is caused by a heterozygous mutation, Glu325Lys (E325K), in the KLF1 transcription factor. A molecular understanding of this disease is absent, partly due to its rarity. We expanded erythroid cells from a patient’s peripheral blood and analyzed its global expression pattern. We find that a large number of erythroid pathways are disrupted, particularly those related to membrane transport, globin regulation, and iron utilization. The altered genetics lead to significant deficits in differentiation. Glu325 is within the KLF1 zinc finger domain at an amino acid critical for site specific DNA binding. The change to Lys is predicted to significantly alter the target site recognition sequence, both by subverting normal recognition and by enabling interaction with novel sites. Consistent with this, we find high level ectopic expression of genes not normally present in the red cell. These altered properties explain the patients’ clinical and phenotypic features and elucidate the dominant character of the mutation.

2019-03-23 | GSE128718 | GEO

Gene expression profile of erythroblastic cells induced from congenital dyserythropoietic anemia (CDA) patient-derived induced pluripotent stem cells

Project description:Analysis of erythroblastic cells differentiated from induced pluripotent stem cells (iPSCs) generated from peripheral blood T lymphocytes of CDA type IV patient. Type IV congenital dyserythropoietic anemia (CDA) is due to a monoallelic mutation at the second zinc finger of KLF1 (c.973G>A). Results provide insight into molecular mechanisms underlying CDA pathogenesis.

2019-03-04 | GSE102985 | GEO

Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient.

Project description:Congenital dyserythropoietic anemia type IV is caused by a heterozygous mutation, Glu325Lys (E325K), in the KLF1 transcription factor. Molecular characteristics of this disease have not been clarified, partly due to its rarity. We expanded erythroid cells from a patient's peripheral blood and analyzed its global expression pattern. We find that a large number of erythroid pathways are disrupted, particularly those related to membrane transport, globin regulation, and iron utilization. The altered genetics lead to significant deficits in differentiation. Glu325 is within the KLF1 zinc finger domain at an amino acid critical for site specific DNA binding. The change to Lys is predicted to significantly alter the target site recognition sequence, both by subverting normal recognition and by enabling interaction with novel sites. Consistent with this, we find high level ectopic expression of genes not normally present in the red cell. These altered properties explain patients' clinical and phenotypic features, and elucidate the dominant character of the mutation.

| S-EPMC6959163 | biostudies-literature

KLF1 null neonates display hydrops fetalis and a deranged erythroid transcriptome

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

RNA-sequencing comparing activation of wild-type transcription factor KLF1 with mutant KLF1 (KLF1-325K) in iPSC-derived macrophages.

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.

2023-03-31 | GSE228537 | GEO

A Congenital Anemia Dissociates the Pleiotropic Functions of Master Transcription Factor GATA1 [Patient scRNA-seq]

Project description:A Congenital Anemia Dissociates the Pleiotropic Functions of Master Transcription Factor GATA1 [Patient scRNA-seq]

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A Congenital Anemia Dissociates the Pleiotropic Functions of Master Transcription Factor GATA1 [Patient Cut&Run]

Project description:A Congenital Anemia Dissociates the Pleiotropic Functions of Master Transcription Factor GATA1 [Patient Cut&Run]

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A Congenital Anemia Dissociates the Pleiotropic Functions of Master Transcription Factor GATA1 [Patient scATAC-seq]

Project description:A Congenital Anemia Dissociates the Pleiotropic Functions of Master Transcription Factor GATA1 [Patient scATAC-seq]

| PRJNA649167 | ENA

Novel roles for Klf1 in regulating the erythroid transcriptome revealed by mRNA-seq

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

Congenital Anemia Phenotypes Due to KLF1 Mutations.

Project description: Not available

| S-EPMC7736060 | biostudies-literature