The splicing factor Sf3b1 regulates erythroid maturation and proliferation via TGFb signaling in zebrafish

Adriana De La Garza, Rosannah C. Cameron, Varun Gupta, Ellen Fraint, Sara Nik, Teresa V. Bowman

Research output: Contribution to journalArticle

Abstract

The spliceosomal component Splicing Factor 3B, subunit 1 (SF3B1) is one of the most prevalently mutated factors in the bone marrow failure disorder myelodysplastic syndrome. There is a strong clinical correlation between SF3B1 mutations and erythroid defects, such as refractory anemia with ringed sideroblasts, but the role of SF3B1 in normal erythroid development is largely unknown. Loss-of-function zebrafish mutants for sf3b1 develop a macrocytic anemia. Here, we explore the underlying mechanism for anemia associated with sf3b1 deficiency in vivo. We found that sf3b1 mutant erythroid progenitors display a G0/G1 cell-cycle arrest with mutant erythrocytes showing signs of immaturity. RNA-sequencing analysis of sf3b1 mutant erythroid progenitors revealed normal expression of red blood cell regulators such as gata1, globin genes, and heme biosynthetic factors, but upregulation of genes in the transforming growth factor b (TGFb) pathway. As TGFb signaling is a known inducer of quiescence, the data suggest that activation of the pathway could trigger sf3b1 deficiency-induced anemia via cell-cycle arrest. Indeed, we found that inhibition of TGFb signaling released the G0/G1 block in erythroid progenitors. Surprisingly, removal of this checkpoint enhanced rather than suppressed the anemia, indicating that the TGFb-mediated cell-cycle arrest is protective for sf3b1-mutant erythrocytes. Together, these data suggest that macrocytic anemia arising from Sf3b1 deficiency is likely due to pleiotropic and distinct effects on cell-cycle progression and maturation.

Original languageEnglish (US)
Pages (from-to)2093-2104
Number of pages12
JournalBlood Advances
Volume3
Issue number14
DOIs
StatePublished - Jul 23 2019

ASJC Scopus subject areas

  • Hematology

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