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The RNA Binding Protein IGF2BP2 is Upregulated by Stress in the Heart and Causes Mitochondrial Dysfunction and Dilated Cardiomyopathy

ABSTRACT: The IGF2BP family of RNA binding proteins consists of three paralogs, IGF2BP1, 2, and 3, that regulate RNA function at many levels, including intracellular RNA localization, RNA stability, and translational control. Although IGF2BP1 and 3 are oncofetal proteins, IGF2BP2 expression is maintained in many tissues, including the heart, into adulthood. Several previous studies indicated that IGF2BP2 is upregulated in cardiomyocytes during cardiac stress and remodelling and returns to normal levels in recovering hearts. These results suggested that IGF2BP2 might play an adaptive role during cardiac stress and recovery. To investigate the role of IGF2BP2 in the heart, we made use of a conditional, inducible transgenic mouse line. Enhanced expression of the IGF2BP2 transgene in hearts of newborn or adult mice leads to dilated cardiomyopathy (DCM), with remodelling, fibrosis, and death occurring within 3-4 weeks. Turning off expression of the transgene after 2 weeks, however, rescues these mice, and they recover completely by 12 weeks. Proteomic analysis identified a downregulation of sarcomeric and mitochondrial proteins in hearts overexpressing IGF2BP2, and electron microscopy revealed fragmented mitochondria and elongated, thinner sarcomeres, suggesting a possible mechanism of action. Consistent with these results, IGF2BP2 is upregulated in patients with DCM or after myocardial infarction. These results show that cardiac stress upregulates IGF2BP2, and this upregulation causes remodelling and compensation of the heart. Prolonged IGF2BP2 expression, however, leads to heart failure and death, making it an attractive target for therapeutic intervention.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Hanan Schoffman

LAB HEAD: Joel K. Yisraeli

PROVIDER: PXD037623 | Pride | 2024-01-26

REPOSITORIES: Pride

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RNA binding protein IGF2BP2 expression is induced by stress in the heart and mediates dilated cardiomyopathy.

Krumbein Miriam M Oberman Froma F Cinnamon Yuval Y Golomb Mordechai M May Dalit D Vainer Gilad G Belzer Vitali V Meir Karen K Fridman Irina I Haybaeck Johannes J Poelzl Gerhard G Kehat Izhak I Beeri Ronen R Kessler Sonja M SM Yisraeli Joel K JK

Communications biology 20231205 1

The IGF2BP family of RNA binding proteins consists of three paralogs that regulate intracellular RNA localization, RNA stability, and translational control. Although IGF2BP1 and 3 are oncofetal proteins, IGF2BP2 expression is maintained in many tissues, including the heart, into adulthood. IGF2BP2 is upregulated in cardiomyocytes during cardiac stress and remodeling and returns to normal levels in recovering hearts. We wondered whether IGF2BP2 might play an adaptive role during cardiac stress an ...[more]

PMID: 38052926

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Project description:To investigate molecular mechanisms involved in the development of cardiac hypertrophy and heart failure, a tetracycline-regulated transgenic system to conditionally switch a constitutively-active form of the Akt1 protein kinase on or off in the adult heart was developed. Short-term activation (2 weeks) of Akt1 resulted in completely reversible hypertrophy with maintained contractility. In contrast, chronic Akt1 activation (6 weeks) induced extensive cardiac hypertrophy, severe contractile dysfunction, and massive interstitial fibrosis. The focus of this study was to create a transcript expression profile of the heart as it undergoes reversible Akt1-mediated hypertrophy and during the transition from compensated hypertrophy to heart failure. Heart tissue was analyzed before transgene induction, 2 weeks after transgene induction, 2 weeks of transgene induction followed by 2 days of repression, 6 weeks after transgene induction and 6 weeks of transgene induction followed by 2 weeks of repression. Acute over expression of Akt1 (2 weeks) leads to changes in the expression of 826 transcripts relative to non-induced hearts, whereas chronic induction (6 weeks) led to changes in the expression of 1611, of which 65% represented transcripts that were regulated during the pathological phase of heart growth. Another set of genes identified were uniquely regulated during heart regression but not growth, indicating that non-overlapping transcription programs participate in the processes of cardiac hypertrophy and atrophy. These data define the gene regulatory programs downstream of Akt that control heart size and contribute to the transition from compensatory hypertrophy to heart failure. Experiment Overall Design: Gene expression data from DTG-positive mouse hearts were examined before the induction of the transgene Akt1 (time point 1), 2 weeks after the induction of the transgene Akt1(time point 2), 2 weeks after the induction of the transgene Akt1 and 2 days after the repression of the transgene Akt1 (time point 3), 6 weeks after the induction of the transgene Akt1(time point 4) and 6 weeks after the induction of the transgene Akt1 and 2 weeks after the repression of the transgene Akt1 (time point 5). N = 3 to 4 sets of independent hybridizations from individual mice were performed for each time point.

Project description:Background: Modulation of mRNA splicing acts as an important layer of gene regulation, in addition to transcriptional regulation and epigenetic modifications. RNA binding proteins (RBPs) play essential roles in mediating RNA splicing and are key regulators of heart development and function. Our previous studies demonstrated that RBPMS (RNA-binding protein with multiple splicing) regulates cardiac development through modulating mRNA splicing during embryogenesis. Here we explored the postnatal function of RBPMS in the heart. Methods: We ablated Rbpms in the heart by generating a cardiac-specific knockout mouse line (Myh6-Cre, Rbpmsfl/fl), and evaluated its cardiac functions by histology, echocardiography, and gene expression. Paired-end RNA sequencing and RT-PCR were performed to identify and validate splicing targets of RBPMS in adult mouse hearts. Proximity-dependent Biotin Identification (BioID) assay and mass spectrometry analysis were performed to identify RBPMS binding partners. We also measured contractility and calcium fluxes in isolated mouse cardiomyocytes, and contractile forces of cardiac papillary muscle. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) were also used as a model to explore the influence of RBPMS on contractility of human cardiomyocytes. Results: he absence of Rbpms in the heart led to dilated cardiomyopathy (DCM) and heart failure, causing early death in mice. Mice with cardiac-specific knockout of Rbpms showed myocardium noncompaction with reduced cardiomyocyte number at the neonatal stage and developed DCM with pervasive myocardial fibrosis in adulthood. We found that RBPMS mediates a largely distinct RNA splicing profile in adult mouse hearts compared to neonatal hearts, indicating a stage-specific modulation of alternative RNA splicing by RBPMS. In adult hearts, RBPMS mainly influenced alternative splicing of genes associated with sarcomere structures and cardiomyocyte contraction, such as Ttn, Pdlim5 and Nexn, to generate new protein isoforms. In neonatal hearts, RBPMS influenced the splicing of cytoskeletal genes. RBMPS was associated with spliceosome factors and other RNA binding proteins that play important roles in the heart, such as RBM20 and GATA4. Importantly, we found that the absence of Rbpms caused severe cardiomyocyte contractile defects and reduced calcium sensitivity in both mouse and hiPSC-CMs. Our results demonstrated that Rbpms is crucial for postnatal cardiac function and cardiomyocyte contractility by regulating RNA alternative splicing. Conclusions: Loss of Rbpms in the heart causes reduced cardiomyocyte number and impaired cardiomyocyte contraction, leading to DCM and heart failure.

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