Transcription Factors KLF1 and KLF2 Positively Regulate Embryonic and Fetal β-Globin Genes through Direct Promoter Binding

Alhashem, Yousef N.; Vinjamur, Divya S.; Basu, Mohua; Klingmüller, Ursula; Gaensler, Karin; Lloyd, Joyce A.

doi:10.1074/jbc.m111.247536

Cited by 41 publications

(48 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, transcripts encoding myeloperoxidase and lysozyme, involved in differentiation of more mature myeloid stages, were strongly downregulated, in agreement with the incomplete myeloid development observed in EGFP þ Tie2-Cre;N1ICD cells. 43 Despite the marked alteration in erythropoiesis observed in Tie2-Cre;N1ICD embryos, the transcription of Klf1 and Klf2, important genes in this process 46 did not show variations. Constitutive Notch1 activation in Tie2-derived cells thus dysregulates the transcriptional program that initiates the first differentiation steps in early hematopoietic progenitor cells and some lineage-restricted precursors.…”

Section: E)mentioning

confidence: 97%

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

et al. 2014

View full text Add to dashboard Cite

Loss-of-function studies have demonstrated the essential role of Notch in definitive embryonic mouse hematopoiesis. We report here the consequences of Notch gain-of-function in mouse embryo hematopoiesis, achieved by constitutive expression of Notch1 intracellular domain (N1ICD) in angiopoietin receptor tyrosine kinase receptor-2 (Tie2)-derived enhanced green fluorescence protein (EGFP þ ) hematovascular progenitors. At E9.5, N1ICD expression led to the absence of the dorsal aorta hematopoietic clusters and of definitive hematopoiesis. The EGFP þ transient multipotent progenitors, purified from E9.5 to 10.5 Tie2-Cre;N1ICD yolk sac (YS) cells, had strongly reduced hematopoietic potential, whereas they had increased numbers of hemogenic endothelial cells. Late erythroid cell differentiation stages and mature myeloid cells (Gr1 þ , MPO þ ) were also strongly decreased. In contrast, EGFP þ erythro-myeloid progenitors, immature and intermediate differentiation stages of YS erythroid and myeloid cell lineages, were expanded. Tie2-Cre;N1ICD YS had reduced numbers of CD41 þ þ megakaryocytes, and these produced reduced below-normal numbers of immature colonies in vitro and their terminal differentiation was blocked. Cells from Tie2-Cre;N1ICD YS had a higher proliferation rate and lower apoptosis than wild-type (WT) YS cells. Quantitative gene expression analysis of FACS-purified EGFP þ YS progenitors revealed upregulation of Notch1-related genes and alterations in genes involved in hematopoietic differentiation. These results represent the first in vivo evidence of a role for Notch signaling in YS transient definitive hematopoiesis. Our results show that constitutive Notch1 activation in Tie2 þ cells hampers YS hematopoiesis of E9.5 embryos and demonstrate that Notch signaling regulates this process by balancing the proliferation and differentiation dynamics of lineage-restricted intermediate progenitors.

show abstract

Section: E)mentioning

confidence: 97%

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

et al. 2014

View full text Add to dashboard Cite

show abstract

“…20 Wholemount embryos were photographed with an Olympus SZ2-ILSTmicroscope (Olympus America, Center Valley, PA, USA), using an Olympus Q-Color 3 camera and QCapture 2.81.0 software (Quantitative Imaging, Surrey, BC, USA). Embryonic yolk sacs were embedded and sectioned as previously described.…”

Section: Tissue Collection and Processingmentioning

confidence: 99%

“…In order to determine whether the anemia observed in KLF1-/-KLF2-/-embryos results from erythroid cell-specific ablation of KLF2, the ideal mouse model would be an erythroid conditional knockout of KLF2 on a KLF1 null background. Unfortunately, Cre expression under the control of the erythroid-specific erythropoietin receptor (EpoR) promoter in ErGFP-Cre mice 20,34 is dependent on KLF1 (Online Supplementary Figure S1). Consequently, this model was untenable.…”

Section: Klf1/klf2 Double Conditional Ko Embryos Recapitulate the Klfmentioning

confidence: 99%

“…KLF2 is necessary for primitive erythropoiesis, and positively regulates embryonic globin gene expression, as shown in KLF2 knockout and erythroid-conditional knockout mouse embryos. 11,19,20 Global gene expression assays indicate that many genes that are important in the processes of development, differentiation and cell migration are dysregulated in KLF2-/-compared to wild-type primitive erythroid cells. 21 Ablation of KLF2 causes lethality between E11.5 and E14.…”

Section: Introductionmentioning

confidence: 99%

“…cDNA synthesis and quantitative reverse-transcriptase PCR (qRT-PCR) were performed as previously described. 11,12,19,20 Primer sequences for qRT-PCR are listed in Online Supplementary Table S1.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Kruppel-like transcription factors KLF1 and KLF2 have unique and coordinate roles in regulating embryonic erythroid precursor maturation

et al. 2014

View full text Add to dashboard Cite

The Krüppel-like transcription factors KLF1 and KLF2 are essential for embryonic erythropoiesis. They can partially compensate for each other during mouse development, and coordinately regulate numerous erythroid genes, including the b-like globins. Simultaneous ablation of KLF1 and KLF2 results in earlier embryonic lethality and severe anemia. In this study, we determine that this anemia is caused by a paucity of blood cells, and exacerbated by diminished b-like globin gene expression. The anemia phenotype is dose-dependent, and, interestingly, can be ameliorated by a single copy of the KLF2, but not the KLF1 gene. The roles of KLF1 and KLF2 in maintaining normal peripheral blood cell numbers and globin mRNA amounts are erythroid cell-specific. Mechanistic studies led to the discovery that KLF2 has an essential function in erythroid precursor maintenance. KLF1 can partially compensate for KLF2 in this role, but is uniquely crucial for erythroid precursor proliferation through its regulation of G1-to S-phase cell cycle transition. A more drastic impairment of primitive erythroid colony formation from embryonic progenitor cells occurs with simultaneous loss of KLF1 and KLF2 than with loss of a single factor. KLF1 and KLF2 coordinately regulate several proliferation-associated genes, including Foxm1. Differential expression of FoxM1, in particular, correlates with the observed KLF1 and KLF2 gene dosage effects on anemia. Furthermore, KLF1 binds to the FoxM1 gene promoter in blood cells. Thus KLF1 and KLF2 coordinately regulate embryonic erythroid precursor maturation through the regulation of multiple homeostasis-associated genes, and KLF2 has a novel and essential role in this process.

show abstract

Gene therapies for transfusion dependent β‐thalassemia: Current status and critical criteria for success

Soni

2020

American J Hematol

View full text Add to dashboard Cite

Thalassemia is one of the most prevalent monogenic diseases usually caused by quantitative defects in the production of β‐globin leading to severe anemia. Technological advances in genome sequencing, stem cell selection, viral vector development, transduction and gene editing strategies now allow for efficient ex‐vivo genetic manipulation of human stem cells that can lead to production of hemoglobin, leading to a meaningful clinical benefit in thalassemia patients. In this review, the status of the gene‐therapy approaches available for transfusion dependent thalassemia are discussed, along with the critical criteria that affect efficacy and lessons that have been learned from the early phase clinical trials. Salient steps necessary for the clinical development, manufacturing, and regulatory approvals of gene therapies for thalassemia are also highlighted, so that the potential of these therapies can be realized. It is highly anticipated that gene therapies will soon become a treatment option for patients lacking compatible donors for hematopoietic stem cell transplant and will offer an alternative for definitive treatment of β‐thalassemia.

show abstract

Transcription Factors KLF1 and KLF2 Positively Regulate Embryonic and Fetal β-Globin Genes through Direct Promoter Binding

Cited by 41 publications

References 56 publications

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

Kruppel-like transcription factors KLF1 and KLF2 have unique and coordinate roles in regulating embryonic erythroid precursor maturation

Gene therapies for transfusion dependent β‐thalassemia: Current status and critical criteria for success

Contact Info

Product

Resources

About