Faculty Collaboration Database

GATA/Heme Multi-omics Reveals a Trace Metal-Dependent Cellular Differentiation Mechanism. Dev Cell 2018 Sep 10;46(5):581-594.e4

Date

08/21/2018

Pubmed ID

30122630

Pubmed Central ID

PMC6133724

DOI

10.1016/j.devcel.2018.07.022

Scopus ID

2-s2.0-85053858322 (requires institutional sign-in at Scopus site)   29 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.

Author List

Tanimura N, Liao R, Wilson GM, Dent MR, Cao M, Burstyn JN, Hematti P, Liu X, Zhang Y, Zheng Y, Keles S, Xu J, Coon JJ, Bresnick EH

Author

Peiman Hematti MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Carrier Proteins
Cell Differentiation
Cells, Cultured
Erythroblasts
Erythropoiesis
Female
GATA1 Transcription Factor
Gene Expression Regulation
Heme
Male
Mice
Mice, Inbred C57BL
Proteome
Transcriptome
Zinc