4 Scopus citations

Abstract

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.

Original languageEnglish
Article number111830
JournalCell Reports
Volume41
Issue number12
DOIs
StatePublished - 20 Dec 2022

Keywords

  • CBP
  • CP: Molecular biology
  • ChIP-seq
  • EKLF/Klf1
  • H3K27ac
  • Nan
  • RNA polymerase
  • elongation
  • erythropoiesis
  • pausing
  • pioneering
  • transcription

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