Bclaf1 Drives Heart Failure by Recruiting Srsf2 to Enhance Hand2 Pre-mRNA Splicing and Pathological Hypertrophy
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Heart
SUBMITTER: 
yang zhang
LAB HEAD: yang zhang
PROVIDER: PXD077261 | Pride | 2026-05-27
REPOSITORIES: Pride
Dataset's files
| Action | DRS | |||
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| Match_result-X101SC19093128_Z01_J002_B1_43.zip | Other | |||
| Raw_file-X101SC19093128_Z01_J002_B1_43.zip | Other | |||
| checksum.txt | Txt |
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2025-05-06 | PXD045161 | Pride
Project description:Mutations within genes encoding spliceosomal proteins are the most common class of mutations in patients with myelodysplastic syndromes, yet it is currently not well understood how these mutations impact hematopoiesis or RNA splicing. Here we report that mutations affecting the splicing factor SRSF2 alter its normal RNA recognition activity, resulting in impaired hematopoietic differentiation and myelodysplasia. Commonly occurring SRSF2 mutations impaired wildtype SRSF2’s normal RNA-binding avidity and preference for specific exonic splicing enhancer RNA motifs. Integration of murine and human transcriptome data identified recurrent mis-splicing of key transcriptional regulators in the presence of mutant SRSF2, including promotion of a highly conserved “poison” exon of EZH2 that results in nonsense-mediated decay and contributes to impaired hematopoiesis. These data provide a mechanistic basis for the enrichment of specific mutations in spliceosomal proteins in myelodysplasia, and suggest that altered RNA recognition activity is a novel mechanism of leukemogenesis. mRNA profiles of murine model and K562 cells expressing SRSF2 WT, mutants and knockdown of SRSF2 in TF-1 cells generated by deep sequencing.
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Project description:Heart failure (HF) impacts 2-3% of adults in the West, with prevalence rising with age. This condition, leading to high mortality and morbidity, increasingly involves HF with preserved left ventricular (LV) ejection fraction (HFpEF) in the aging population, having a similar stable prognosis as HF with reduced LVEF (HFrEF). However, HFpEF lacks many evidence-based therapies, partly due to its distinct pathophysiology compared to HFrEF. Molecularly, heart failure shows distinct gene expression changes, indicative of varying diseases. Prior research, including our early report from the CABG-PREFERS study, shows gene expression differences in HFpEF and normal hearts, although studies are limited. Both HFpEF and HFrEF patients exhibit altered LV myocardial structure and function, often affecting the right ventricle (RV) secondarily. In the CABG-PREFERS sub-study, part of the PREFERS programme, we classified patients by LVEF, structural abnormalities, diastolic dysfunction, and NT-proBNP levels into HFpEF physiology, HFrEF physiology, and normal LV function groups. Our hypothesis suggests gene expression and transcriptomic variations between LV and RV, and between HFpEF, HFrEF, and normal LV function, providing insights into different HF phenotypes and guiding future therapies.
2024-02-28 | E-MTAB-13553 | biostudies-arrayexpress
Project description:<p>Background: Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired contractility and high mortality. Dysregulation of intracellular ion cycling underlies the decline in cardiac contractility. Modulation of cardiac Na+/H+ and Ca2+ handling is considered a valuable approach for restoring cardiac function; thus, an in-depth understanding of the molecular regulation is timely for the discovery of new strategies to treat HFrEF.</p><p>Methods: Cardiac tissues from HFrEF patients and mice subjected to transverse aortic constriction (TAC) were analyzed for sterol regulatory element-binding protein 1 (SREBP1) transactivation of Sodium-hydrogen exchanger 3 (NHE3).Cardiomyocyte-specific SREBP1 transgenic (Srebp1a-Tg) and knockdown (Cre-Srebp1f/f) mice were generated. AAV9 vectors carrying Slc9a3 (encoding NHE3), Srebf1 or shRNA against Slc9a3, driven by the cardiomyocyte-specific cTnT promoter, were used to validate the role of the SREBP1-NHE3 in HFrEF. </p><p>Results: SREBP1 was activated in human hearts with HFrEF (dilated cardiomyopathy without diabetes or hyperlipidemia) and in mouse hearts with TAC-induced HFrEF. Srebp1a-Tg mice exhibited impaired cardiac contractilitywith dysregulated calcium handling in cardiomyocytes without apparent lipid accumulation. Transcriptomics analysis, ChIP-seq, ChIP assay, and promoter activity assessment showed that Slc9a3 (encoding NHE3) is a transcriptional target of SREBP1. Consistently, NHE3 was upregulated in Srebp1a-Tg mouse hearts, hearts under TAC surgery, and human failing hearts. Cardiomyocyte-specific knockdown of Srebp1 or Slc9a3 restored calcium handling and improved cardiac function in TAC hearts. In Srebp1a-Tg mice, NHE3 knockdown alleviated Na+ and Ca2+ overload and rescued cardiac systolic dysfunction. Conversely, NHE3 overexpression caused contractile impairment in both Cre-Srebp1f/f mice and controls, which offset the protective effect due to SREBP1 loss in the context of Na+ and Ca2+ overload. These resultsdemonstrate that SREBP1 upregulation of NHE3 caused cardiac dysfunction. Notably, empagliflozin downregulated NHE3 via AMP-activated protein kinase activation and inhibition of SREBP1, which ameliorated calcium overload and restored cardiac systolic function.</p><p>Conclusions: SREBP1 transactivates cardiac NHE3 expression during the progression of HFrEF, leading to dysregulatedcalcium handling and impaired contractility, suggesting a non-canonical role of SREBP1 in heart failure. Empagliflozin mitigates these detrimental effects by inhibiting the cardiac SREBP1-NHE3 axis, thus revealing a new pharmacological mechanism by which SGLT2i alleviates HF.</p>
2026-02-20 | MTBLS13690 | MetaboLights
Project description:<p>Background: Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired contractility and high mortality. Dysregulation of intracellular ion cycling underlies the decline in cardiac contractility. Modulation of cardiac Na+/H+ and Ca2+ handling is considered a valuable approach for restoring cardiac function; thus, an in-depth understanding of the molecular regulation is timely for the discovery of new strategies to treat HFrEF.</p><p>Methods: Cardiac tissues from HFrEF patients and mice subjected to transverse aortic constriction (TAC) were analyzed for sterol regulatory element-binding protein 1 (SREBP1) transactivation of Sodium-hydrogen exchanger 3 (NHE3).Cardiomyocyte-specific SREBP1 transgenic (Srebp1a-Tg) and knockdown (Cre-Srebp1f/f) mice were generated. AAV9 vectors carrying Slc9a3 (encoding NHE3), Srebf1 or shRNA against Slc9a3, driven by the cardiomyocyte-specific cTnT promoter, were used to validate the role of the SREBP1-NHE3 in HFrEF. </p><p>Results: SREBP1 was activated in human hearts with HFrEF (dilated cardiomyopathy without diabetes or hyperlipidemia) and in mouse hearts with TAC-induced HFrEF. Srebp1a-Tg mice exhibited impaired cardiac contractilitywith dysregulated calcium handling in cardiomyocytes without apparent lipid accumulation. Transcriptomics analysis, ChIP-seq, ChIP assay, and promoter activity assessment showed that Slc9a3 (encoding NHE3) is a transcriptional target of SREBP1. Consistently, NHE3 was upregulated in Srebp1a-Tg mouse hearts, hearts under TAC surgery, and human failing hearts. Cardiomyocyte-specific knockdown of Srebp1 or Slc9a3 restored calcium handling and improved cardiac function in TAC hearts. In Srebp1a-Tg mice, NHE3 knockdown alleviated Na+ and Ca2+ overload and rescued cardiac systolic dysfunction. Conversely, NHE3 overexpression caused contractile impairment in both Cre-Srebp1f/f mice and controls, which offset the protective effect due to SREBP1 loss in the context of Na+ and Ca2+ overload. These resultsdemonstrate that SREBP1 upregulation of NHE3 caused cardiac dysfunction. Notably, empagliflozin downregulated NHE3 via AMP-activated protein kinase activation and inhibition of SREBP1, which ameliorated calcium overload and restored cardiac systolic function.</p><p>Conclusions: SREBP1 transactivates cardiac NHE3 expression during the progression of HFrEF, leading to dysregulatedcalcium handling and impaired contractility, suggesting a non-canonical role of SREBP1 in heart failure. Empagliflozin mitigates these detrimental effects by inhibiting the cardiac SREBP1-NHE3 axis, thus revealing a new pharmacological mechanism by which SGLT2i alleviates HF.</p>
2026-02-20 | MTBLS13701 | MetaboLights
Project description:<p>Background: Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired contractility and high mortality. Dysregulation of intracellular ion cycling underlies the decline in cardiac contractility. Modulation of cardiac Na+/H+ and Ca2+ handling is considered a valuable approach for restoring cardiac function; thus, an in-depth understanding of the molecular regulation is timely for the discovery of new strategies to treat HFrEF.</p><p>Methods: Cardiac tissues from HFrEF patients and mice subjected to transverse aortic constriction (TAC) were analyzed for sterol regulatory element-binding protein 1 (SREBP1) transactivation of Sodium-hydrogen exchanger 3 (NHE3).Cardiomyocyte-specific SREBP1 transgenic (Srebp1a-Tg) and knockdown (Cre-Srebp1f/f) mice were generated. AAV9 vectors carrying Slc9a3 (encoding NHE3), Srebf1 or shRNA against Slc9a3, driven by the cardiomyocyte-specific cTnT promoter, were used to validate the role of the SREBP1-NHE3 in HFrEF. </p><p>Results: SREBP1 was activated in human hearts with HFrEF (dilated cardiomyopathy without diabetes or hyperlipidemia) and in mouse hearts with TAC-induced HFrEF. Srebp1a-Tg mice exhibited impaired cardiac contractilitywith dysregulated calcium handling in cardiomyocytes without apparent lipid accumulation. Transcriptomics analysis, ChIP-seq, ChIP assay, and promoter activity assessment showed that Slc9a3 (encoding NHE3) is a transcriptional target of SREBP1. Consistently, NHE3 was upregulated in Srebp1a-Tg mouse hearts, hearts under TAC surgery, and human failing hearts. Cardiomyocyte-specific knockdown of Srebp1 or Slc9a3 restored calcium handling and improved cardiac function in TAC hearts. In Srebp1a-Tg mice, NHE3 knockdown alleviated Na+ and Ca2+ overload and rescued cardiac systolic dysfunction. Conversely, NHE3 overexpression caused contractile impairment in both Cre-Srebp1f/f mice and controls, which offset the protective effect due to SREBP1 loss in the context of Na+ and Ca2+ overload. These resultsdemonstrate that SREBP1 upregulation of NHE3 caused cardiac dysfunction. Notably, empagliflozin downregulated NHE3 via AMP-activated protein kinase activation and inhibition of SREBP1, which ameliorated calcium overload and restored cardiac systolic function.</p><p>Conclusions: SREBP1 transactivates cardiac NHE3 expression during the progression of HFrEF, leading to dysregulatedcalcium handling and impaired contractility, suggesting a non-canonical role of SREBP1 in heart failure. Empagliflozin mitigates these detrimental effects by inhibiting the cardiac SREBP1-NHE3 axis, thus revealing a new pharmacological mechanism by which SGLT2i alleviates HF.</p>
2026-02-20 | MTBLS13696 | MetaboLights