GATA/Heme Multi-omics Reveals a Trace Metal-Dependent Cellular Differentiation Mechanism

Nobuyuki Tanimura, Ruiqi Liao, Gary M. Wilson, Matthew R. Dent, Miao Cao, Judith N. Burstyn, Peiman Hematti, Xin Liu, Yuannyu Zhang, Ye Zheng, Sunduz Keles, Jian Xu, Joshua J. Coon, Emery H. Bresnick

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

By functioning as an enzyme cofactor, hemoglobin component, and gene regulator, heme is vital for life. One mode of heme-regulated transcription involves amplifying the activity of GATA-1, a key determinant of erythrocyte differentiation. To discover biological consequences of the metal cofactor-transcription factor mechanism, we merged GATA-1/heme-regulated sectors of the proteome and transcriptome. This multi-omic analysis revealed a GATA-1/heme circuit involving hemoglobin subunits, ubiquitination components, and proteins not implicated in erythrocyte biology, including the zinc exporter Slc30a1. Though GATA-1 induced expression of Slc30a1 and the zinc importer Slc39a8, Slc39a8 dominantly increased intracellular zinc, which conferred erythroblast survival. Subsequently, a zinc transporter switch, involving decreased importer and sustained exporter expression, reduced intracellular zinc during terminal differentiation. Downregulating Slc30a1 increased intracellular zinc and, strikingly, accelerated differentiation. This analysis established a conserved paradigm in which a GATA-1/heme circuit controls trace metal transport machinery and trace metal levels as a mechanism governing cellular differentiation. Zinc deficiency causes anemia through poorly understood mechanisms. Tanimura et al. report that GATA-1, a major determinant of red blood cell development, and heme, an essential cofactor for hemoglobin synthesis, control zinc levels. Zinc levels in turn regulate red blood cell development, thereby establishing a paradigm that informs anemia mechanisms.

Original languageEnglish (US)
Pages (from-to)581-594.e4
JournalDevelopmental cell
Volume46
Issue number5
DOIs
StatePublished - Sep 10 2018

Keywords

  • GATA
  • differentiation
  • erythrocyte
  • proteome
  • trace metal
  • transcriptome
  • zinc

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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    Tanimura, N., Liao, R., Wilson, G. M., Dent, M. R., Cao, M., Burstyn, J. N., Hematti, P., Liu, X., Zhang, Y., Zheng, Y., Keles, S., Xu, J., Coon, J. J., & Bresnick, E. H. (2018). GATA/Heme Multi-omics Reveals a Trace Metal-Dependent Cellular Differentiation Mechanism. Developmental cell, 46(5), 581-594.e4. https://doi.org/10.1016/j.devcel.2018.07.022