Haem‐regulated eIF2α kinase is necessary for adaptive gene expression in erythroid precursors under the stress of iron deficiency

Haem‐regulated eIF2α 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.

[1]  Raffaella Origa,et al.  BETA THALASSEMIA , 2018, The Professional Medical Journal.

[2]  S. Philipsen,et al.  Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropoiesis. , 2008, Blood.

[3]  N. Andrews,et al.  The function of heme-regulated eIF2alpha kinase in murine iron homeostasis and macrophage maturation. , 2007, The Journal of clinical investigation.

[4]  D. Saur,et al.  Translational Repression of MCL-1 Couples Stress-induced eIF2α Phosphorylation to Mitochondrial Apoptosis Initiation* , 2007, Journal of Biological Chemistry.

[5]  S. Ghaffari,et al.  Foxo3 is required for the regulation of oxidative stress in erythropoiesis. , 2007, The Journal of clinical investigation.

[6]  Jane-Jane Chen.  Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. , 2007, Blood.

[7]  Olivier Hermine,et al.  Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1 , 2007, Nature.

[8]  N. Andrews,et al.  Iron homeostasis. , 2007, Annual review of physiology.

[9]  K. Fung,et al.  Effect of arsenic trioxide on multidrug resistant hepatocellular carcinoma cells. , 2006, Cancer letters.

[10]  Tohru Kimura,et al.  Differential effects of GATA-1 on proliferation and differentiation of erythroid lineage cells. , 2006, Blood.

[11]  M. Fleming,et al.  Heme-regulated eIF2α kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and β-thalassemia , 2005 .

[12]  N. Sonenberg,et al.  Translational control in stress and apoptosis , 2005, Nature Reviews Molecular Cell Biology.

[13]  Masayuki Yamamoto,et al.  GATA1 Function, a Paradigm for Transcription Factors in Hematopoiesis , 2005, Molecular and Cellular Biology.

[14]  J. Crispino,et al.  GATA1 in normal and malignant hematopoiesis. , 2005, Seminars in cell & developmental biology.

[15]  S. Orkin,et al.  Coregulation of GATA factors by the Friend of GATA (FOG) family of multitype zinc finger proteins. , 2005, Seminars in cell & developmental biology.

[16]  E. Rachmilewitz,et al.  MEDICAL PROGRESS : β-thalassemia , 2005 .

[17]  M. Fleming,et al.  Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia. , 2005, The Journal of clinical investigation.

[18]  Hao Wang,et al.  Global regulation of erythroid gene expression by transcription factor GATA-1. , 2004, Blood.

[19]  Harvey F Lodish,et al.  Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system. , 2003, Blood.

[20]  Jae K. Lee,et al.  Local-pooled-error test for identifying differentially expressed genes with a small number of replicated microarrays , 2003, Bioinform..

[21]  R. Stoltzfus.  Iron Deficiency: Global Prevalence and Consequences , 2003, Food and nutrition bulletin.

[22]  S. Orkin,et al.  X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. , 2002, Blood.

[23]  S. Orkin,et al.  Targeted Deletion of a High-Affinity GATA-binding Site in the GATA-1 Promoter Leads to Selective Loss of the Eosinophil Lineage In Vivo , 2002, The Journal of experimental medicine.

[24]  J. Bieker,et al.  The BMP/BMPR/Smad pathway directs expression of the erythroid-specific EKLF and GATA1 transcription factors during embryoid body differentiation in serum-free media. , 2002, Development.

[25]  S. Orkin,et al.  Heme‐regulated eIF2α kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency , 2001, The EMBO journal.

[26]  Y. Benjamini,et al.  Controlling the false discovery rate in behavior genetics research , 2001, Behavioural Brain Research.

[27]  C. Trainor,et al.  A GATA Box in the GATA-1 Gene Hematopoietic Enhancer Is a Critical Element in the Network of GATA Factors and Sites That Regulate This Gene , 2000, Molecular and Cellular Biology.

[28]  S. Srinivasula,et al.  Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1 , 1999, Nature.

[29]  Y Fujiwara,et al.  Different sequence requirements for expression in erythroid and megakaryocytic cells within a regulatory element upstream of the GATA-1 gene. , 1999, Development.

[30]  S. Orkin,et al.  Use of altered specificity mutants to probe a specific protein-protein interaction in differentiation: the GATA-1:FOG complex. , 1999, Molecular cell.

[31]  O. Nakajima,et al.  Role of GATA-1 in proliferation and differentiation of definitive erythroid and megakaryocytic cells in vivo. , 1998, Blood.

[32]  S. Orkin,et al.  Failure of megakaryopoiesis and arrested erythropoiesis in mice lacking the GATA-1 transcriptional cofactor FOG. , 1998, Genes & development.

[33]  S. Orkin,et al.  FOG, a Multitype Zinc Finger Protein, Acts as a Cofactor for Transcription Factor GATA-1 in Erythroid and Megakaryocytic Differentiation , 1997, Cell.

[34]  S. Orkin,et al.  A "knockdown" mutation created by cis-element gene targeting reveals the dependence of erythroid cell maturation on the level of transcription factor GATA-1. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  S. Klinken,et al.  Lyn tyrosine kinase is essential for erythropoietin‐induced differentiation of J2E erythroid cells , 1997, The EMBO journal.

[36]  S. Orkin,et al.  Erythroid-cell-specific properties of transcription factor GATA-1 revealed by phenotypic rescue of a gene-targeted cell line , 1997, Molecular and cellular biology.

[37]  Y Fujiwara,et al.  Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[38]  G. Keller,et al.  Novel insights into erythroid development revealed through in vitro differentiation of GATA-1 embryonic stem cells. , 1994, Genes & development.

[39]  S. Orkin,et al.  Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1 , 1991, Nature.