RBPMS regulates cardiomyocyte contraction and cardiac function through RNA alternative splicing.
RBPMS regulates cardiomyocyte contraction and cardiac function through RNA alternative splicing.
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RBPMS 通过 RNA 选择性剪接调节心肌细胞收缩和心脏功能。
DOI：
10.1093/cvr/cvad166
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发表时间：
2024
影响因子：
10.8
通讯作者：
Olson,EricN
中科院分区：
文献类型：
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作者：
Gan,Peiheng;Wang,Zhaoning;Bezprozvannaya,Svetlana;McAnally,JohnR;Tan,Wei;Li,Hui;Bassel-Duby,Rhonda;Liu,Ning;Olson,EricN
AimsRNA结合蛋白在介导RNA剪接中发挥重要作用，是心脏中关键的转录后调节因子。我们最近的研究表明，RBPMS（RNA结合蛋白与多剪接）是至关重要的心脏发育，通过调节mRNA剪接，但很少有人知道它在成人心脏的功能。在这项研究中，我们的目的是表征出生后的心脏功能的Rbpms及其机制的action.Methods和resultsWe产生了一个心脏特异性基因敲除小鼠线，发现心脏特异性损失的Rbpms引起严重的心肌细胞收缩缺陷，导致扩张型心肌病和早期致死性成年小鼠。我们通过邻近依赖性生物素鉴定试验和质谱分析表明，RBPMS与剪接体因子和其他RNA结合蛋白（如RBM 20）相关，这些蛋白在心脏功能中很重要。我们进行了配对末端RNA测序和RT-PCR，发现RBPMS调节与肌节结构和功能相关的基因的mRNA选择性剪接，如Ttn，Pdlim 5和Nexn，产生新的蛋白质异构体。使用小基因剪接报告基因分析，我们确定RBPMS通过识别串联内含子CAC基序来调节靶基因剪接。我们还表明，在人类诱导多能干细胞衍生的心肌细胞RBPMS敲低损害心肌cardiomyocyte contraction.ConclusionThis研究确定RBPMS作为一个重要的调节器，通过调节肌节基因选择性剪接的心肌细胞收缩和心脏功能。
AimsRNA binding proteins play essential roles in mediating RNA splicing and are key post-transcriptional regulators in the heart. Our recent study demonstrated that RBPMS (RNA binding protein with multiple splicing) is crucial for cardiac development through modulating mRNA splicing, but little is known about its functions in the adult heart. In this study, we aim to characterize the post-natal cardiac function ofRbpmsand its mechanism of action.Methods and resultsWe generated a cardiac-specific knockout mouse line and found that cardiac-specific loss ofRbpmscaused severe cardiomyocyte contractile defects, leading to dilated cardiomyopathy and early lethality in adult mice. We showed by proximity-dependent biotin identification assay and mass spectrometry that RBPMS associates with spliceosome factors and other RNA binding proteins, such as RBM20, that are important in cardiac function. We performed paired-end RNA sequencing and RT–PCR and found that RBPMS regulates mRNA alternative splicing of genes associated with sarcomere structure and function, such asTtn,Pdlim5, andNexn, generating new protein isoforms. Using a minigene splicing reporter assay, we determined that RBPMS regulates target gene splicing through recognizing tandem intronic CAC motifs. We also showed thatRBPMSknockdown in human induced pluripotent stem cell-derived cardiomyocytes impaired cardiomyocyte contraction.ConclusionThis study identifies RBPMS as an important regulator of cardiomyocyte contraction and cardiac function by modulating sarcomeric gene alternative splicing.