The Zebrafish moonshine Gene Encodes Transcriptional Intermediary Factor 1γ, an Essential Regulator of Hematopoiesis

Abstract

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 1γ (TIF1γ) (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 tif1γ mRNA rescues embryonic hematopoiesis in homozygous mon mutants. Surprisingly, a high level of zygotic tif1γ mRNA expression delineates ventral mesoderm during hematopoietic stem cell and progenitor formation prior to gata1 expression. Transplantation studies reveal that tif1γ functions in a cell-autonomous manner during the differentiation of erythroid precursors. Studies in murine erythroid cell lines demonstrate that Tif1γ 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.

The role of Smad signaling in hematopoiesis and translational hematology

“…Interestingly, the zebrafish homolog of TIF1g, encoded by moonshine, has been shown to be essential for blood formation with mutants displaying severe red cell aplasia, indicating that the function of TIF1g may be preserved across species. 41 Furthermore, Bai et al 42 recently uncovered a role for TIF1g in regulating transcription elongation of erythroid genes. The model proposed suggests that TIF1g functions to release paused Pol II at erythroid genes by recruiting positive elongation factors to the blood-specific transcriptional complex, thus promoting transcription.…”

Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma

“…TRIM24 is the founding member of a conserved subfamily of TIF1α-related TRIM proteins with orthologues from Drosophila to human (9-13) that play crucial roles in many physiological processes including cell differentiation, development, and tissue homeostasis (12,(14)(15)(16)(17)(18)(19)(20)(21)(22). Members of this subfamily share a common N-terminal TRIM previously known as a RING-Bbox-coiled-coil (RBCC) motif and a chromatin binding unit comprising a C-terminal plant homeo domain finger and bromodomain that act as a single functional unit to promote recognition of a combination of unmethylated lysine 4 of histone H3 (H3K4me0) and acetylated H3K23 (23).…”

“…Different members of the TIF1 family interact with distinct transcription factors; ligand activated nuclear receptors or p53 [TRIM24 (29, 30)], Krüppel-associated box domain-containing zinc finger proteins [TRIM28, (31)], and transforming growth factor (TGF)-β receptor-activated mothers against decapentaplegic (SMAD) and coSMAD proteins [tripartite motif 33 (TRIM33) also known as transcriptional intermediary factor 1 gamma (TIF1γ); (12,17,18)]. TRIM33 acts on the TGF-β pathway either as a monoubiquitin ligase for SMAD4 and/or as a cofactor for phosphorylated SMAD2/3 (17, 32), whereas it is also reported to act directly on the transcription initiation complex by promoting recruitment of positive transcription elongation factor b and the facilitates chromatin transcription (FACT) complex to counteract RNA polymerase II pausing (33).…”

TIF1γ : un gène suppresseur de tumeur dans la leucémie myélomonocytaire chronique

“…Son rôle est majeur au cours de l'embryogenèse puisque sa délétion génique est létale [1,2]. Chez le poisson zèbre, une mutation du gène tif1 perturbe spéci-fiquement l'hématopoïèse embryonnaire et adulte [3,4]. Différentes fonctions de TIF1 ont été décrites également au cours de l'hématopoïèse, tant chez la souris que chez l'homme.…”

“…Cette même accumulation de proérythroblastes est retrouvée dans un modèle in vitro de différenciation érythrocytaire à partir de cellules CD34 + humaines dans lesquelles TIF1 a été inhibé par une stratégie d'interférence ARN [3,4]. Les fonctions moléculaires de TIF1 restent controversées.…”