The PAX-SIX-EYA-DACH network modulates GATA-FOG function in fly hematopoiesis and human erythropoiesis

T. Michael Creed, Rajkumar Baldeosingh, Christian L. Eberly, Caroline S. Schlee, Min Jung Kim, Jevon A. Cutler, Akhilesh Pandey, Curt I. Civin, Nancy G. Fossett, Tami J. Kingsbury

Research output: Contribution to journalArticle

Abstract

The GATA and PAX-SIX-EYA-DACH transcriptional networks (PSEDNs) are essential for proper development across taxa. Here, we demonstrate novel PSEDN roles in vivo in Drosophila hematopoiesis and in human erythropoiesis in vitro Using Drosophila genetics, we show that PSEDN members function with GATA to block lamellocyte differentiation and maintain the prohemocyte pool. Overexpression of human SIX1 stimulated erythroid differentiation of human erythroleukemia TF1 cells and primary hematopoietic stem-progenitor cells. Conversely, SIX1 knockout impaired erythropoiesis in both cell types. SIX1 stimulation of erythropoiesis required GATA1, as SIX1 overexpression failed to drive erythroid phenotypes and gene expression patterns in GATA1 knockout cells. SIX1 can associate with GATA1 and stimulate GATA1-mediated gene transcription, suggesting that SIX1-GATA1 physical interactions contribute to the observed functional interactions. In addition, both fly and human SIX proteins regulated GATA protein levels. Collectively, our findings demonstrate that SIX proteins enhance GATA function at multiple levels, and reveal evolutionarily conserved cooperation between the GATA and PSEDN networks that may regulate developmental processes beyond hematopoiesis.

Original languageEnglish (US)
JournalDevelopment (Cambridge, England)
Volume147
Issue number1
DOIs
StatePublished - Jan 3 2020

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Keywords

  • GATA
  • Hematopoiesis
  • PAX-SIX-EYA-DACH network
  • Retinal determination gene network
  • SIX1
  • SIX2

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

Creed, T. M., Baldeosingh, R., Eberly, C. L., Schlee, C. S., Kim, M. J., Cutler, J. A., Pandey, A., Civin, C. I., Fossett, N. G., & Kingsbury, T. J. (2020). The PAX-SIX-EYA-DACH network modulates GATA-FOG function in fly hematopoiesis and human erythropoiesis. Development (Cambridge, England), 147(1). https://doi.org/10.1242/dev.177022