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

Dev Cell. 2018 Sep 10;46(5):581-594.e4. doi: 10.1016/j.devcel.2018.07.022. Epub 2018 Aug 16.

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.

Keywords: GATA; differentiation; erythrocyte; proteome; trace metal; transcriptome; zinc.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Differentiation / drug effects*
  • Cells, Cultured
  • Erythroblasts / cytology*
  • Erythroblasts / drug effects
  • Erythroblasts / metabolism
  • Erythropoiesis / drug effects
  • Female
  • GATA1 Transcription Factor / genetics
  • GATA1 Transcription Factor / metabolism*
  • Gene Expression Regulation / drug effects
  • Heme / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proteome
  • Transcriptome
  • Zinc / pharmacology*

Substances

  • Carrier Proteins
  • GATA1 Transcription Factor
  • Gata1 protein, mouse
  • Proteome
  • zinc-binding protein
  • Heme
  • Zinc