ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells

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. In order to further investigate the role of this splice factor in RNA splicing and hema...

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Main Authors: Madan, Vikas, Cao, Zeya, Teoh, Weoi Woon, Dakle, Pushkar, Han, Lin, Shyamsunder, Pavithra, Jeitany, Maya, Zhou, Siqin, Li, Jia, Hazimah Mohd Nordin, Shi, JiZhong, Yu, Shuizhou, Yang, Henry, Md Zakir Hossain, Chng, Wee Joo, Koeffler, H Phillip
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2022
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Online Access:https://hdl.handle.net/10356/162693
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Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-162693
record_format dspace
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Protein P53
Hematopoietic Cell
spellingShingle Science::Medicine
Protein P53
Hematopoietic Cell
Madan, Vikas
Cao, Zeya
Teoh, Weoi Woon
Dakle, Pushkar
Han, Lin
Shyamsunder, Pavithra
Jeitany, Maya
Zhou, Siqin
Li, Jia
Hazimah Mohd Nordin
Shi, JiZhong
Yu, Shuizhou
Yang, Henry
Md Zakir Hossain
Chng, Wee Joo
Koeffler, H Phillip
ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells
description 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. In order to further investigate the role of this splice factor in RNA 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 in human cells 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 accurately model ZRSR2-mutant MDS in mice.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Madan, Vikas
Cao, Zeya
Teoh, Weoi Woon
Dakle, Pushkar
Han, Lin
Shyamsunder, Pavithra
Jeitany, Maya
Zhou, Siqin
Li, Jia
Hazimah Mohd Nordin
Shi, JiZhong
Yu, Shuizhou
Yang, Henry
Md Zakir Hossain
Chng, Wee Joo
Koeffler, H Phillip
format Article
author Madan, Vikas
Cao, Zeya
Teoh, Weoi Woon
Dakle, Pushkar
Han, Lin
Shyamsunder, Pavithra
Jeitany, Maya
Zhou, Siqin
Li, Jia
Hazimah Mohd Nordin
Shi, JiZhong
Yu, Shuizhou
Yang, Henry
Md Zakir Hossain
Chng, Wee Joo
Koeffler, H Phillip
author_sort Madan, Vikas
title ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells
title_short ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells
title_full ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells
title_fullStr ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells
title_full_unstemmed ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells
title_sort zrsr1 co-operates with zrsr2 in regulating splicing of u12-type introns in murine hematopoietic cells
publishDate 2022
url https://hdl.handle.net/10356/162693
_version_ 1759854671121350656
spelling sg-ntu-dr.10356-1626932023-02-28T17:12:23Z ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells Madan, Vikas Cao, Zeya Teoh, Weoi Woon Dakle, Pushkar Han, Lin Shyamsunder, Pavithra Jeitany, Maya Zhou, Siqin Li, Jia Hazimah Mohd Nordin Shi, JiZhong Yu, Shuizhou Yang, Henry Md Zakir Hossain Chng, Wee Joo Koeffler, H Phillip School of Biological Sciences Cancer Science Institute of Singapore, NUS Science::Medicine Protein P53 Hematopoietic Cell 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. In order to further investigate the role of this splice factor in RNA 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 in human cells 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 accurately model ZRSR2-mutant MDS in mice. Ministry of Education (MOE) Ministry of Health (MOH) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work was funded by the Leukemia and Lymphoma Society, the Singapore Ministry of Health’s National Medical Research Council (NMRC) under its Singapore Translational Research (STaR) Investigator Award to HPK (NMRC/STaR/0021/2014), the NMRC Center Grant awarded to the National University Cancer Institute of Singapore (NMRC/CG/012/2013) and the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiatives. This research is also supported by the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education’s Tier 3 grants, grant number MOE2014-T3-1-006. We thank the Melamed Family for their generous support. 2022-11-07T01:23:25Z 2022-11-07T01:23:25Z 2022 Journal Article Madan, V., Cao, Z., Teoh, W. W., Dakle, P., Han, L., Shyamsunder, P., Jeitany, M., Zhou, S., Li, J., Hazimah Mohd Nordin, Shi, J., Yu, S., Yang, H., Md Zakir Hossain, Chng, W. J. & Koeffler, H. P. (2022). ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells. Haematologica, 107(3), 680-689. https://dx.doi.org/10.3324/haematol.2020.260562 0390-6078 https://hdl.handle.net/10356/162693 10.3324/haematol.2020.260562 33691379 2-s2.0-85125553217 3 107 680 689 en NMRC/CG/012/2013 MOE2014-T3-1-006 Haematologica © 2022 Ferrata Storti Foundation. Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher. application/pdf