PT  - JOURNAL ARTICLE
AU  - Tomasz Dobrzycki
AU  - Christopher B. Mahony
AU  - Monika Krecsmarik
AU  - Cansu Koyunlar
AU  - Rossella Rispoli
AU  - Joke Peulen-Zink
AU  - Kirsten Gussinklo
AU  - Bakhta Fedlaoui
AU  - Emma de Pater
AU  - Roger Patient
AU  - Rui Monteiro
TI  - Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult haematopoiesis
AID  - 10.1101/516203
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 516203
4099  - http://biorxiv.org/content/early/2019/12/10/516203.short
4100  - http://biorxiv.org/content/early/2019/12/10/516203.full
AB  - Haematopoietic stem and progenitor cells (HSPCs) maintain the vertebrate blood system throughout life and their emergence from haemogenic endothelium (HE) is regulated by transcription factors such as Gata2. Here we deleted a conserved enhancer (i4 enhancer) driving pan-endothelial expression of gata2a and showed that Gata2a is required for HE programming by regulating expression of runx1 and of the second zebrafish 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 HE programming in embryos and maintenance of steady-state haematopoietic stem cell output in the adult. These enhancer mutants are a new paradigm to explore the pathophysiology of GATA2-related deficiencies in vivo.