Biology subjects

Landstrom, A. P.

Publications and source records attributed to Landstrom, A. P..

3 recordsLinked to original sources

bioRxiv2026

Cardiomyocyte vulnerability to lamin polymer disruption revealed by saturation mutagenesis

Hundreds of mutations to the broadly expressed LMNA gene cause disease primarily within cardiac, muscular, and adipose tissues (1). Tissue-specific pathogenesis arises when mutant protein dysfunction collides with the unique demands of a specific cell type. Here, we decipher the cell-type-specific consequences of ~15,000 LMNA mutations by completing the first saturation mutagenesis screens in human induced pluripotent cells (hiPSCs) and hiPSC-derived cardiomyocytes using our newly developed single large serine integrase cassette exchange (SLICE) platform. We find that destabilization is a predominant consequence of pathogenic LMNA mutations, is selected against in human populations, and is associated with cardiomyopathy. Mutation sensitivity maps reveal Lamin A quality control at both the subunit and multimer level, resolve lateral and head-to-tail polymerization interfaces, and uncover a convergence between disruption of lamin polymer assembly and pathogenesis. Uniquely in cardiomyocytes, lamin A polymer assembly defects drive profound protein loss, nuclear abnormalities, and cellular toxicity, explaining the origins of cardiac specificity in laminopathy syndromes.

cell biology↗

bioRxiv2026

Perm1 Gene Therapy Mitigates PRDM16-Associated Cardiomyopathy

BackgroundPathogenic variants in PR domain containing 16 (PRDM16) cause pediatric and adult cardiomyopathies characterized by ventricular dilation, systolic dysfunction, and impaired metabolic maturation. Cardiac deficiency of PRDM16 alters metabolic gene expression and long-chain fatty acid (FA) metabolites. However, the downstream mediators involved are not well characterized. Furthermore, whether improving mitochondrial FA metabolism can prevent PRDM16-associated cardiomyopathy is currently unknown. MethodsIn vivo and in vitro approaches using patient-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and mouse models with Prdm16 deletion/mutation were employed. Transcriptomics and proteomics analyses were conducted, and adeno-associated virus (AAV)-mediated therapy was tested. ResultsHere, we show that a defect in FA metabolism is an early hallmark of PRDM16 cardiac deficiency. We show, for the first time, that PERM1 is a direct downstream target of PRDM16 and is involved in the regulation of FA metabolism through coordinated action with PGC1. Most importantly, neonatal delivery of AAV9-Perm1 in cardiac-specific Prdm16 knockout (Prdm16 cKO) mice markedly improved contractile parameters, reduced left ventricular (LV) dilation, and extended survival. These cardioprotective effects of PERM1 gene therapy occurred independent of restoring FA oxidation. Transcriptional and proteomic analyses of AAV-Perm1-treated Prdm16 cKO mice demonstrated significant improvements in mitochondrial cristae architecture, preservation of sarcomere organization, reduced cardiomyocyte apoptosis, attenuated myocardial fibrosis, and diminished cardiac remodeling. ConclusionsWe identify PERM1 as a direct downstream effector of PRDM16 and uncover a previously unrecognized PRDM16-PGC1-PERM1 axis essential for FA metabolic regulation in the heart. Perm1 gene therapy ameliorated PRDM16-associated cardiomyopathy through post-transcriptional mechanisms involving preservation of mitochondrial and sarcomere integrity. The current study provides preclinical evidence suggesting that Perm1 gene therapy may be a promising therapeutic target to improve the cardiac outcomes of patients affected by pathogenic PRDM16 variants.

physiology↗

bioRxiv2025

A gene regulatory element modulates myosin expression and controls cardiomyocyte response to stress

A hallmark of heart disease is gene dysregulation and reactivation of fetal gene programs. Reactivation of these fetal programs has compensatory effects during heart failure, depending on the type and stage of the underlying cardiomyopathy. Thousands of putative cardiac gene regulatory elements have been identified that may control these programs, but their functions are largely unknown. We profile genome-wide changes to gene expression and chromatin structure in cardiomyocytes derived from human pluripotent stem cells. We identify and characterize a gene regulatory element essential for the regulation of MYH6, which encodes human fetal myosin. Using chromatin conformation assays in combination with epigenome editing, we find that gene regulation is mediated by direct interaction between MYH6 and the enhancer. We also find that enhancer activation alters cardiomyocyte response to the hypertrophy-inducing peptide endothelin-1. Enhancer activation prevents polyploidization and changes in calcium dynamics following stress with endothelin-1. Collectively, these results identify regulatory mechanisms of cardiac gene expression programs that modulate cardiomyocyte maturation, cellular stress response, and could serve as potential therapeutic targets.

genomics↗