TY - JOUR
T1 - Z-band and M-band titin splicing and regulation by RNA binding motif 20 in striated muscles
AU - Chen, Zhilong
AU - Maimaiti, Rexiati
AU - Zhu, Chaoqun
AU - Cai, Hanfang
AU - Stern, Allysa
AU - Mozdziak, Paul
AU - Ge, Ying
AU - Ford, Stephen P.
AU - Nathanielsz, Peter W.
AU - Guo, Wei
N1 - Funding Information:
This work was supported by the National Institute of Health/National Institute of General Medical Sciences (NIGMSP20GM103432); the BGIA from the American Heart Association (16BGIA27790136 to W Guo); the USDA National Institute of Food and Agriculture (Hatch Project 1009266 to W Guo); NICHD HD070096 (SP Ford and PW Nathaniels). Y Ge would like to acknowledge NIH R01 HL109810 and HL096971. We gratefully thank Dan Levy at the University of Wyoming to provide frog heart tissues and David M. Hanna for the animal care and laboratory management. We thank the Chinese Scholarship Council (CSC, Beijing, China) to support Z Chen. We also thank Drs. Paul Mozdziak and Peter W.
Funding Information:
This work was supported by the National Institute of Health/National Institute of General Medical Sciences (NIGMSP20GM103432); the BGIA from the American Heart Association (16BGIA27790136 to W Guo); the USDA National Institute of Food and Agriculture (Hatch Project 1009266 to W Guo); NICHD HD070096 (SP Ford and PW Nathaniels). Y Ge would like to acknowledge NIH R01 HL109810 and HL096971. We gratefully thank Dan Levy at the University of Wyoming to provide frog heart tissues and David M. Hanna for the animal care and laboratory management. We thank the Chinese Scholarship Council (CSC, Beijing, China) to support Z Chen. We also thank Drs. Paul Mozdziak and Peter W. Nathanielsz for their critical reading and corrections on grammatical errors.
PY - 2018/12
Y1 - 2018/12
N2 - Titin (TTN) has multifunctional roles in sarcomere assembly, mechanosignaling transduction, and muscle stiffness. TTN splicing generates variable protein sizes with different functions. Therefore, understanding TTN splicing is important to develop a novel treatment for TTN-based diseases. The I-band TTN splicing regulated by RNA binding motif 20 (RBM20) has been extensively studied. However, the Z- and M-band splicing and regulation remain poorly understood. Herein, we aimed to define the Z- and M-band splicing in striated muscles and determined whether RBM20 regulates the Z- and M-band splicing. We discovered four new Z-band TTN splicing variants, and one of them dominates in mouse, rat, sheep, and human hearts. But only one form can be detected in frog and chicken hearts. In skeletal muscles, three new Z repeats (Zr) were detected, and Zr4 to 6 exclusion dominates in the fast muscles, whereas Zr4 skipping dominates in the slow muscle. No developmental changes were detected in the Z-band. In the M-band, two new variants were discovered with alternative 3′ splice site in exon363 (Mex5) and alternative 5′ splice site in intron 362. However, only the sheep heart expresses two new variants rather than other species. Skeletal muscles express three M-band variants with altered ratios of Mex5 inclusion to Mex5 exclusion. Finally, we revealed that RBM20 does not regulate the Z- and M-band splicing in the heart, but does in skeletal muscles. Taken together, we characterized the Z- and M-band splicing and provided the first evidence of the role of RBM20 in the Z- and M-band TTN splicing.
AB - Titin (TTN) has multifunctional roles in sarcomere assembly, mechanosignaling transduction, and muscle stiffness. TTN splicing generates variable protein sizes with different functions. Therefore, understanding TTN splicing is important to develop a novel treatment for TTN-based diseases. The I-band TTN splicing regulated by RNA binding motif 20 (RBM20) has been extensively studied. However, the Z- and M-band splicing and regulation remain poorly understood. Herein, we aimed to define the Z- and M-band splicing in striated muscles and determined whether RBM20 regulates the Z- and M-band splicing. We discovered four new Z-band TTN splicing variants, and one of them dominates in mouse, rat, sheep, and human hearts. But only one form can be detected in frog and chicken hearts. In skeletal muscles, three new Z repeats (Zr) were detected, and Zr4 to 6 exclusion dominates in the fast muscles, whereas Zr4 skipping dominates in the slow muscle. No developmental changes were detected in the Z-band. In the M-band, two new variants were discovered with alternative 3′ splice site in exon363 (Mex5) and alternative 5′ splice site in intron 362. However, only the sheep heart expresses two new variants rather than other species. Skeletal muscles express three M-band variants with altered ratios of Mex5 inclusion to Mex5 exclusion. Finally, we revealed that RBM20 does not regulate the Z- and M-band splicing in the heart, but does in skeletal muscles. Taken together, we characterized the Z- and M-band splicing and provided the first evidence of the role of RBM20 in the Z- and M-band TTN splicing.
KW - M-band
KW - RNA binding motif 20 (RBM20)
KW - Z-band
KW - alternative splicing
KW - heart disease
KW - titin (TTN)
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U2 - 10.1002/jcb.27328
DO - 10.1002/jcb.27328
M3 - Article
C2 - 30133019
AN - SCOPUS:85052660111
VL - 119
SP - 9986
EP - 9996
JO - Journal of Cellular Biochemistry
JF - Journal of Cellular Biochemistry
SN - 0730-2312
IS - 12
ER -