title: Zebrafish globin switching occurs in two developmental stages and is controlled by the LCR.
abstract: Globin gene switching is a complex, highly regulated process allowing expression of distinct globin genes at specific developmental stages. Here, for the first time, we have characterized all of the zebrafish globins based on the completed genomic sequence. Two distinct chromosomal loci, termed major (chromosome 3) and minor (chromosome 12), harbor the globin genes containing α/β pairs in a 5'-3' to 3'-5' orientation. Both these loci share synteny with the mammalian α-globin locus. Zebrafish globin expression was assayed during development and demonstrated two globin switches, similar to human development. A conserved regulatory element, the locus control region (LCR), was revealed by analyzing DNase I hypersensitive sites, H3K4 trimethylation marks and GATA1 binding sites. Surprisingly, the position of these sites with relation to the globin genes is evolutionarily conserved, despite a lack of overall sequence conservation. Motifs within the zebrafish LCR include CACCC, GATA, and NFE2 sites, suggesting functional interactions with known transcription factors but not the same LCR architecture. Functional homology to the mammalian α-LCR MCS-R2 region was confirmed by robust and specific reporter expression in erythrocytes of transgenic zebrafish. Our studies provide a comprehensive characterization of the zebrafish globin loci and clarify the regulation of globin switching.
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, and Harvard Stem Cell Institute, Harvard Medical School, 1 Blackfan Cir., Karp 7, Boston, MA 02115, USA. jganis@fas.harvard.edu
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Ganis
authors.forename: Nelson
authors.initials: N
authors.lastname: Hsia
authors.forename: Eirini
authors.initials: E
authors.lastname: Trompouki
authors.forename: Jill L O
authors.initials: JL
authors.lastname: de Jong
authors.forename: Anthony
authors.initials: A
authors.lastname: DiBiase
authors.forename: Janelle S
authors.initials: JS
authors.lastname: Lambert
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Jia
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sabo
authors.forename: Molly
authors.initials: M
authors.lastname: Weaver
authors.forename: Richard
authors.initials: R
authors.lastname: Sandstrom
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
mesh_terms: D000818:Animals; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000502:physiology; D050982:GATA1 Transcription Factor / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005812:Genes, Switch; D005914:Globins / Q000235:genetics*; D019901:Locus Control Region / Q000235:genetics*; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D050982:GATA1 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; D029961:Zebrafish Proteins; C494691:gata1a protein, zebrafish; C494694:nfe2 protein, zebrafish; D005914:Globins