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 language | English (US) |
|---|---|
| Pages (from-to) | 581-594.e4 |
| Journal | Developmental Cell |
| Volume | 46 |
| Issue number | 5 |
| DOIs | |
| State | Published - Sep 10 2018 |
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Keywords
- differentiation
- erythrocyte
- GATA
- proteome
- trace metal
- transcriptome
- zinc
ASJC Scopus subject areas
- Developmental Biology
Cite this
GATA/Heme Multi-omics Reveals a Trace Metal-Dependent Cellular Differentiation Mechanism. / Tanimura, Nobuyuki; Liao, Ruiqi; Wilson, Gary M.; Dent, Matthew R.; Cao, Miao; Burstyn, Judith N.; Hematti, Peiman; Liu, Xin; Zhang, Yuannyu; Zheng, Ye; Keles, Sunduz; Xu, Jian; Coon, Joshua J.; Bresnick, Emery H.
In: Developmental Cell, Vol. 46, No. 5, 10.09.2018, p. 581-594.e4.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - GATA/Heme Multi-omics Reveals a Trace Metal-Dependent Cellular Differentiation Mechanism
AU - Tanimura, Nobuyuki
AU - Liao, Ruiqi
AU - Wilson, Gary M.
AU - Dent, Matthew R.
AU - Cao, Miao
AU - Burstyn, Judith N.
AU - Hematti, Peiman
AU - Liu, Xin
AU - Zhang, Yuannyu
AU - Zheng, Ye
AU - Keles, Sunduz
AU - Xu, Jian
AU - Coon, Joshua J.
AU - Bresnick, Emery H.
PY - 2018/9/10
Y1 - 2018/9/10
N2 - 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.
AB - 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.
KW - differentiation
KW - erythrocyte
KW - GATA
KW - proteome
KW - trace metal
KW - transcriptome
KW - zinc
UR - http://www.scopus.com/inward/record.url?scp=85053858322&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053858322&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2018.07.022
DO - 10.1016/j.devcel.2018.07.022
M3 - Article
C2 - 30122630
AN - SCOPUS:85053858322
VL - 46
SP - 581-594.e4
JO - Developmental Cell
JF - Developmental Cell
SN - 1534-5807
IS - 5
ER -