Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis

Commun Biol. 2020 Feb 13;3(1):71. doi: 10.1038/s42003-020-0798-3.

Abstract

Gata2 is a key transcription factor required to generate Haematopoietic Stem and Progenitor Cells (HSPCs) from haemogenic endothelium (HE); misexpression of Gata2 leads to haematopoietic disorders. Here we deleted a conserved enhancer (i4 enhancer) driving pan-endothelial expression of the zebrafish gata2a and showed that Gata2a is required for HE programming by regulating expression of runx1 and of the second Gata2 orthologue, gata2b. By 5 days, homozygous gata2aΔi4/Δi4 larvae showed normal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b and runx1 expression in HE. However, gata2aΔi4/Δi4 adults showed oedema, susceptibility to infections and marrow hypo-cellularity, consistent with bone marrow failure found in GATA2 deficiency syndromes. Thus, gata2a expression driven by the i4 enhancer is required for correct HE programming in embryos and maintenance of steady-state haematopoietic stem cell output in the adult. These enhancer mutants will be useful in exploring further the pathophysiology of GATA2-related deficiencies in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Base Sequence
  • Cellular Reprogramming / genetics*
  • Chromatin / genetics
  • Conserved Sequence*
  • Endothelium / metabolism*
  • Enhancer Elements, Genetic*
  • GATA2 Transcription Factor / genetics*
  • Gene Expression Regulation, Developmental
  • Genes, Reporter
  • Genetic Loci
  • Hematopoiesis / genetics*
  • Hematopoietic Stem Cells / metabolism
  • Sequence Deletion*
  • Zebrafish

Substances

  • Chromatin
  • GATA2 Transcription Factor