title: Kruppel-like factor 1 (KLF1), KLF2, and Myc control a regulatory network essential for embryonic erythropoiesis.
abstract: The Krüppel-like factor 1 (KLF1) and KLF2 positively regulate embryonic β-globin expression and have additional overlapping roles in embryonic (primitive) erythropoiesis. KLF1(-/-) KLF2(-/-) double knockout mice are anemic at embryonic day 10.5 (E10.5) and die by E11.5, in contrast to single knockouts. To investigate the combined roles of KLF1 and KLF2 in primitive erythropoiesis, expression profiling of E9.5 erythroid cells was performed. A limited number of genes had a significantly decreasing trend of expression in wild-type, KLF1(-/-), and KLF1(-/-) KLF2(-/-) mice. Among these, the gene for Myc (c-Myc) emerged as a central node in the most significant gene network. The expression of the Myc gene is synergistically regulated by KLF1 and KLF2, and both factors bind the Myc promoters. To characterize the role of Myc in primitive erythropoiesis, ablation was performed specifically in mouse embryonic proerythroblast cells. After E9.5, these embryos exhibit an arrest in the normal expansion of circulating red cells and develop anemia, analogous to KLF1(-/-) KLF2(-/-) embryos. In the absence of Myc, circulating erythroid cells do not show the normal increase in α- and β-like globin gene expression but, interestingly, have accelerated erythroid cell maturation between E9.5 and E11.5. This study reveals a novel regulatory network by which KLF1 and KLF2 regulate Myc to control the primitive erythropoietic program.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Pang
authors.forename: Wafaa
authors.initials: W
authors.lastname: Lemsaddek
authors.forename: Yousef N
authors.initials: YN
authors.lastname: Alhashem
authors.forename: Cornelius
authors.initials: C
authors.lastname: Bondzi
authors.forename: Latasha C
authors.initials: LC
authors.lastname: Redmond
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ah-Son
authors.forename: Catherine I
authors.initials: CI
authors.lastname: Dumur
authors.forename: Kellie J
authors.initials: KJ
authors.lastname: Archer
authors.forename: Jack L
authors.initials: JL
authors.lastname: Haar
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Lloyd
authors.forename: Marie
authors.initials: M
authors.lastname: Trudel
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D016259:Genes, myc; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D055542:alpha-Globins / Q000235:genetics; D055544:beta-Globins / Q000235:genetics
chemical_list: D017931:DNA Primers; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D055542:alpha-Globins; D055544:beta-Globins; C080774:erythroid Kruppel-like factor