Haem-regulated eIF2alpha kinase is necessary for adaptive gene expression in erythroid precursors under the stress of iron deficiency.
Haem-regulated eIF2alpha kinase (HRI) is essential for the regulation of globin gene translation and the survival of erythroid precursors in iron/haem deficiency. This study found that that in iron deficiency, fetal definitive erythropoiesis is inhibited at the basophilic erythroblast stage with increased proliferation and elevated apoptosis. This hallmark of ineffective erythropoiesis is more severe in HRI deficiency. Microarray gene profiling analysis showed that HRI was required for adaptive gene expression in erythroid precursors during chronic iron deficiency. The number of genes with expression affected more than twofold increased, from 213 in iron deficiency and 73 in HRI deficiency, to 3135 in combined iron and HRI deficiencies. Many of these genes are regulated by Gata1 and Fog1. We demonstrate for the first time that Gata1 expression in developing erythroid precursors is decreased in iron deficiency, and is decreased further in combined iron and HRI deficiencies. Additionally, Fog1 expression is decreased in combined deficiencies, but not in iron or HRI deficiency alone. Our results indicate that HRI confers adaptive gene expression in developing erythroblasts during iron deficiency through maintaining Gata1/Fog1 expression.
Liu
Sijin
S
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Bhattacharya
Sanchita
S
Han
Anping
A
Suragani
Rajasekhar N V S
RN
Zhao
Wanting
W
Fry
Rebecca C
RC
Chen
Jane-Jane
JJ
D018798:Anemia, Iron-Deficiency / Q000097:blood / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western / Q000379:methods; D002454:Cell Differentiation; D002478:Cells, Cultured; D004920:Erythropoiesis / Q000502:physiology*; D005434:Flow Cytometry; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006418:Heme / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000196:embryology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D012156:Reticulocytes / Q000166:cytology / Q000201:enzymology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism*
D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C498432:ZFPM1 protein, human; D006418:Heme; D019892:eIF-2 Kinase