Open AccessZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells
Author(s) -
Vikas Madan,
Zeya Cao,
Weoi Woon Teoh,
Pushkar Dakle,
Han Lin,
S. Pavithra,
Maya Jeitany,
Shiwei Zhou,
Jia Li,
Hazimah Binte Mohd Nordin,
Shi Jizhong,
Yu Shuizhou,
Henry Yang,
Zakir Hossain,
Wee Joo Chng,
H. Phillip Koeffler
Publication year - 2021
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2020.260562
Subject(s) - biology , intron , spliceosome , genetics , rna splicing , context (archaeology) , myeloid , microbiology and biotechnology , gene , immunology , rna , paleontology
Recurrent loss-of-function mutations of spliceosome gene, ZRSR2, occur in myelodysplastic syndromes (MDS). Mutation/loss of ZRSR2 in human myeloid cells primarily causes impaired splicing of the U12-type introns. To investigate further the role of this splice factor in splicing and hematopoietic development, we generated mice lacking ZRSR2. Unexpectedly, Zrsr2-deficient mice developed normal hematopoiesis with no abnormalities in myeloid differentiation evident in either young or ≥1-year old knockout mice. Repopulation ability of Zrsr2-deficient hematopoietic stem cells was also unaffected in both competitive and non-competitive reconstitution assays. Myeloid progenitors lacking ZRSR2 exhibited mis-splicing of U12-type introns, however, this phenotype was moderate compared to the ZRSR2- deficient human cells. Our investigations revealed that a closely related homolog, Zrsr1, expressed in the murine hematopoietic cells, but not human, contributes to splicing of U12-type introns. Depletion of Zrsr1 in Zrsr2 KO myeloid cells exacerbated retention of the U12-type introns, thus highlighting a collective role of ZRSR1 and ZRSR2 in murine U12-spliceosome. We also demonstrate that aberrant retention of U12-type introns of MAPK9 and MAPK14 leads to their reduced protein expression. Overall, our findings highlight that both ZRSR1 and ZRSR2 are functional components of the murine U12-spliceosome, and depletion of both proteins is required to model accurately ZRSR2-mutant MDS in mice.