1. GATA/Heme Multi-omics Reveals a Trace Metal-Dependent Cellular Differentiation Mechanism
- Author
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Ruiqi Liao, Emery H. Bresnick, Yuannyu Zhang, Jian Xu, Joshua J. Coon, Nobuyuki Tanimura, Matthew R. Dent, Peiman Hematti, Gary M. Wilson, Ye Zheng, Xin Liu, Miao Cao, Judith N. Burstyn, and Sunduz Keles
- Subjects
0301 basic medicine ,Male ,Erythroblasts ,Proteome ,Cellular differentiation ,chemistry.chemical_element ,Zinc ,Heme ,General Biochemistry, Genetics and Molecular Biology ,Cofactor ,Article ,Transcriptome ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Ubiquitin ,Transcription (biology) ,Erythrocyte differentiation ,Animals ,Erythropoiesis ,GATA1 Transcription Factor ,Molecular Biology ,Cells, Cultured ,biology ,Cell Differentiation ,Cell Biology ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,biology.protein ,Female ,Carrier Proteins ,Developmental Biology - 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.
- Published
- 2018