PXD072456

PXD072456 is an original dataset announced via ProteomeXchange.

Title	Enhancing KLF15 Activity in Cardiomyocytes: A Novel Approach to Prevent Pathological Reprogramming and Fibrosis via Nuclease-Deficient dCas9VPR
Description	Transcriptional activity perturbation holds promise for selectively modulating harmful transcriptional networks, but its therapeutic potential remains largely unexplored. We employed a network-based analysis of single-cell heart transcriptomes to identify transcription factor activities linked to pathological cardiomyocytes in vivo. This analysis revealed that transcriptional activity Krueppel-like factor 15 (KLF15) exhibited the most significant change in pathological cardiomyocytes, characterized by less effective repression of pathological genes in stressed hearts, which correlated with reduced KLF15 expression. To restore KLF15 activity, we utilized CRISPR/nuclease-dead (d)Cas9-based transcriptional enhancement (CRISPRa) in cardiomyocytes, which effectively abolished fetal reprogramming by simultaneously suppressing pathological gene expression and restoring metabolic homeostasis under sustained stress conditions. Furthermore, we identified a novel cell-nonautonomous anti-fibrotic effect mediated by cardiomyocyte-fibroblast crosstalk, and revealed the contribution of KLF15-dependent Alpha-2-glycoprotein 1, zinc-binding (AZGP1) regulation in this process. We also elucidated the upstream mechanisms of KLF15 regulation, highlighting its role as a cell-specific downstream target of the broad TGF-β canonical signaling pathway along with its downstream dependent mechanisms in human cardiomyocytes. Finally, to enhance the therapeutic potential of this approach, we engineered and validated an adeno-associated viral (AAV) vector with a small CRISPRa system for endogenous regulation in human cardiomyocytes suitable for clinical applications. Overall, we elucidated a regulatory circuit involving TGF-β, KLF15, and AZGP1, which coordinates critical pathological responses through cellular crosstalk between cardiomyocytes and fibroblasts. Importantly, we demonstrated the efficacy of CRISPRa as epigenetic intervention restoring a critical transcriptional function disrupted in non-genetic heart failure. This approach provides a promising blueprint for future adaptation targeting additional non-hereditary pathologies.
HostingRepository	PRIDE
AnnounceDate	2026-03-09
AnnouncementXML	Submission_2026-03-08_18:59:27.372.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alfredo Cabrera-Orefice
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-28 04:22:23	ID requested
⏵ 1	2026-03-08 18:59:28	announced

10.1038/s41392-026-02593-9;

Schoger E, Kim R, Bleckwedel F, Peralta T, Priesmeier L, Fischer J, Stengel L, Rocha C, Santos GL, Lutz S, Boileau E, Baumgarten N, Schulz MH, Dieterich C, M, ü, ller OJ, Cyganek L, Cabrera-Orefice A, Eberl H, Maack C, Streckfuss-B, ö, meke K, Pavez-Giani M, Doroudgar S, Sossalla ST, Zelaray, á, n LC, Enhancing KLF15 activity in cardiomyocytes: a novel approach to prevent pathological reprogramming and fibrosis via nuclease-deficient dCas9VPR. Signal Transduct Target Ther, 11(1):(2026) [pubmed]

submitter keyword: None

Laura C. Zelarayán
contact affiliation	Institute of Pharmacology & Toxicology, University Medical Center Göttingen, Germany. Medical Clinic I, Department of Cardiology and Angiology, Justus Liebig University, Giessen, Germany. German Centre for Cardiovascular Research (DZHK e.V.), partner sites Lower Saxony, Heidelberg/Mannheim, Munich, Hamburg/Kiel/Lübeck, RhineMain, Germany. Cardio-Pulmonary Institute (CPI), Giessen, Germany.
contact email	laura.zelarayan@med.uni-goettingen.de
lab head
Alfredo Cabrera-Orefice
contact affiliation	Institute of Biochemistry, Justus-Liebig-University Giessen
contact email	alfredbiomed@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/03/PXD072456

PRIDE project URI

• PRIDE
  1. PXD072456
     1. Label: PRIDE project
     2. Name: Enhancing KLF15 Activity in Cardiomyocytes: A Novel Approach to Prevent Pathological Reprogramming and Fibrosis via Nuclease-Deficient dCas9VPR