Identification of a novel, erythroid BKLF promoter

Funnell, Alister P. W.; Keys, Janelle R.; Tallack, Michael R.; Hodge, Denise J.; Perkins, Andrew C.; Crossley, Merlin

doi:10.1016/j.bcmd.2006.10.049

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“…KLF3 has been shown to repress a subset of KLF1 target genes (Funnell et al, 2012) and perhaps even regulates expression of KLF1 itself. KLF3 is expressed throughout the body but is activated in erythropoiesis by KLF1 at an erythroid specific promoter (Funnell et al, 2007b), implying the KLF3 has an important role to play in erythropoiesis.…”

Section: Chapter 5: Klf1 and Klf3 Compete For Promoters And Enhancersmentioning

confidence: 99%

Investigating the Molecular Pathogenesis of Inherited Childhood Anaemia

Ilsley¹

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Krüppel-like factors (KLFs) are a group of 17 transcription factors with diverse functions such as early embryo patterning, organogenesis and tissue homoeostasis. All 17 members contain highlyconserved DNA-binding domains consisting of three C-terminal C2H2-type zinc fingers. This high level of conservation allows all members of the KLF family to bind to a 9 base pair CACCC-box DNA sequence (CCM CRC CCN) which is commonly found in many tissue-specific gene promoters and enhancers. The activity of each member of the KLF family is largely determined by a more variable N-terminal domain through which they interact with co-factors such as p300 and C-terminal binding protein 2 (CtBP2).Many KLFs are often expressed in the same cells. In these situations, they can form transcriptional networks where they coordinate to control developmental programs. For example, KLF2, KLF4, and KLF5 work redundantly in embryonic stem cells where they regulate key pluripotency genes such as Nanog to maintain the 'stemness' of the cell. Multiple KLFs are expressed during erythropoiesis, the ongoing production of red blood cells, where it is likely that they form transcriptional networks to control differentiation.Krüppel-like factor 1 (KLF1) is an erythroid-specific transcription factor that is responsible for coordinating the expression of a large cohort of genes required for nearly all aspects of erythropoiesis. As the founding member of the KLF group, KLF1 contains three C-terminal C2H2-type zinc fingers that bind to DNA and an N-terminal proline-rich activation domain that interacts with co-factors to initiate transcription of target genes.This thesis investigates the molecular mechanisms of Klf1 binding specificity to DNA and how this is affected by mutations, and by competition between family members.A disease that is known as Congenital Dyserythropoietic anaemia type IV (CDAIV) is a rare autosomal-dominant inherited erythrocyte disorder characterised by ineffective erythropoiesis and haemolysis. CDAIV is caused by a point mutation in the second zinc finger of KLF1 which results in substitution of an amino acid predicted to bind to DNA.A mouse carrying a point mutation in the corresponding amino acid residue in murine Klf1 to that mutated in CDAIV patients has been previously generated in an ENU screen. This mouse displays a semi-dominant haemolytic anaemia and is named 'Nan' for 'neonatal anaemia'. The Nan mouse shares a similar phenotype to that of patients with CDAIV and hereditary spherocytosis.Incredibly, both the 'Nan' and CDAIV mutations cause disease which is far more severe than that of commonly occurring Klf1 haploinsufficiency.ii ChIP-seq analysis in cell lines developed to model Klf1 mutations identified aberrant DNAbinding events genome-wide for both the mouse 'Nan' mutation and the human CDAIV mutation.Next-generation sequencing of newly-synthesised RNA (4sU-RNA-seq) reveals ectopic transcriptional consequences of this aberrant binding. Novel sequence specificity of the mutant protein was confirmed by performi...

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Section: Chapter 5: Klf1 and Klf3 Compete For Promoters And Enhancersmentioning

confidence: 99%

Investigating the Molecular Pathogenesis of Inherited Childhood Anaemia

Ilsley¹

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Identification of a novel, erythroid BKLF promoter

Cited by 1 publication

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Investigating the Molecular Pathogenesis of Inherited Childhood Anaemia

Investigating the Molecular Pathogenesis of Inherited Childhood Anaemia

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