A global role for EKLF in definitive and primitive erythropoiesis

Denise Hodge, Elise Coghill, Janelle Keys, Tina Maguire, Belinda Hartmann, Alasdair McDowall, Mitchell Weiss, Sean Grimmond, Andrew Perkins

Research output: Contribution to journalArticleResearchpeer-review

166 Citations (Scopus)

Abstract

Erythroid Kruppel-like factor (EKLF, KLF1) plays an important role in definitive erythropoiesis and β-globin gene regulation but failure to rectify lethal fetal anemia upon correction of globin chain imbalance suggested additional critical EKLF target genes. We employed expression profiling of EKLF-null fetal liver and EKLF-null erythroid cell lines containing an inducible EKLF-estrogen receptor (EKLF-ER) fusion construct to search for such targets. An overlapping list of EKLF-regulated genes from the 2 systems included α-hemoglobin stabilizing protein (AHSP), cytoskeletal proteins, heme-synthesis enzymes, transcription factors, and blood group antigens. One EKLF target gene, dematin, which encodes an erythrocyte cytoskeletal protein (band 4.9), contains several phylogenetically conserved consensus CACC motifs predicted to bind EKLF. Chromatin immunoprecipitation demonstrated in vivo EKLF occupancy at these sites and promoter reporter assays showed that EKLF activates gene transcription through these DNA elements. Furthermore, investigation of EKLF target genes in the yolk sac led to the discovery of unexpected additional defects in the embryonic red cell membrane and cytoskeleton. In short, EKLF regulates global erythroid gene expression that is critical for the development of primitive and definitive red cells.

Original languageEnglish
Pages (from-to)3359-3370
Number of pages12
JournalBlood
Volume107
Issue number8
DOIs
Publication statusPublished - 15 Apr 2006
Externally publishedYes

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