The zebrafish moonshine gene encodes transcriptional intermediary factor 1gamma, an essential regulator of hematopoiesis.
Hematopoiesis is precisely orchestrated by lineage-specific DNA-binding proteins that regulate transcription in concert with coactivators and corepressors. Mutations in the zebrafish moonshine (mon) gene specifically disrupt both embryonic and adult hematopoiesis, resulting in severe red blood cell aplasia. We report that mon encodes the zebrafish ortholog of mammalian transcriptional intermediary factor 1gamma (TIF1gamma) (or TRIM33), a member of the TIF1 family of coactivators and corepressors. During development, hematopoietic progenitor cells in mon mutants fail to express normal levels of hematopoietic transcription factors, including gata1, and undergo apoptosis. Three different mon mutant alleles each encode premature stop codons, and enforced expression of wild-type tif1gamma mRNA rescues embryonic hematopoiesis in homozygous mon mutants. Surprisingly, a high level of zygotic tif1gamma mRNA expression delineates ventral mesoderm during hematopoietic stem cell and progenitor formation prior to gata1 expression. Transplantation studies reveal that tif1gamma functions in a cell-autonomous manner during the differentiation of erythroid precursors. Studies in murine erythroid cell lines demonstrate that Tif1gamma protein is localized within novel nuclear foci, and expression decreases during erythroid cell maturation. Our results establish a major role for this transcriptional intermediary factor in the differentiation of hematopoietic cells in vertebrates.
Division of Hematology/Oncology, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA. zon@enders.tch.harvard.edu
David G
DG
Ransom
Nathan
N
Bahary
Knut
K
Niss
David
D
Traver
Caroline
C
Burns
Nikolaus S
NS
Trede
Noelle
N
Paffett-Lugassy
Walter J
WJ
Saganic
C Anthoney
CA
Lim
Candace
C
Hersey
Yi
Y
Zhou
Bruce A
BA
Barut
Shuo
S
Lin
Paul D
PD
Kingsley
James
J
Palis
Stuart H
SH
Orkin
Leonard I
LI
Zon
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D017690:Cell Transplantation; D003001:Cloning, Molecular; D018388:Codon, Terminator; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry; D004912:Erythrocytes / Q000166:cytology / Q000473:pathology*; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006570:Heterochromatin / Q000378:metabolism; D006720:Homozygote; D015151:Immunoblotting; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*
D018388:Codon, Terminator; D004268:DNA-Binding Proteins; D006570:Heterochromatin; D012333:RNA, Messenger; D014157:Transcription Factors; C491420:Trim33 protein, mouse; D029961:Zebrafish Proteins; C507536:transcriptional intermediary factor 1gamma, zebrafish; D004247:DNA