PT  - JOURNAL ARTICLE
AU  - Jiayi Pei
AU  - Renee G.C. Maas
AU  - Ema Nagyova
AU  - Johannes M.I.H. Gho
AU  - Christian Snijders Blok
AU  - Iris van Adrichem
AU  - Jorg J.A. Calis
AU  - René van Es
AU  - Shahrzad Sepehrkhouy
AU  - Dries Feyen
AU  - Noortje van den Dungen
AU  - Nico Lansu
AU  - Nicolaas de Jonge
AU  - Hester M. den Ruijter
AU  - Manon M.H. Huibers
AU  - Roel A. de Weger
AU  - Linda W. van Laake
AU  - Marianne C. Verhaar
AU  - Peter van Tintelen
AU  - Frank G. van Steenbeek
AU  - Alain van Mil
AU  - Jan W. Buikema
AU  - Boudewijn Burgering
AU  - Ioannis Kararikes
AU  - Mark Mercola
AU  - Pieter A. Doevendans
AU  - Joost Sluijter
AU  - Aryan Vink
AU  - Caroline Cheng
AU  - Michal Mokry
AU  - Folkert W. Asselbergs
AU  - Magdalena Harakalova
TI  - Transcriptional regulation profiling reveals disrupted lipid metabolism in failing hearts with a pathogenic phospholamban mutation
AID  - 10.1101/2020.11.30.402792
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.30.402792
4099  - http://biorxiv.org/content/early/2020/12/01/2020.11.30.402792.short
4100  - http://biorxiv.org/content/early/2020/12/01/2020.11.30.402792.full
AB  - Background The R14del mutation in the phospholamban (PLN) gene is associated with various types of cardiomyopathies and increases the risk of developing life-threatening ventricular arrhythmias. In this study, we focused on a homogeneous Dutch founder cohort of genetic cardiomyopathy due to PLN R14del mutation and aimed to study the influence of epigenetic changes from a multi-dimensional perspective.Results Using cardiac tissue of PLN R14del patients and donors, we identified differentially acetylated promoters and enhancers (H3K27ac ChIPseq), annotated enriched transcription factor (TF) binding motifs located in those regions, and identified differentially expressed genes (RNA-seq). In line with the fibrofatty replacement in PLN R14del hearts at the histological level, our integrative analysis detected the downregulation of key TF regulators in fatty acid oxidation (FAO) metabolisms and their downstream target in PLN R14del hearts as compared to controls. We further examined heart tissue using immunofluorescence staining (IF) and to confirm the mitochondrial lipid abnormalities in the PLN R14del hearts. Furthermore, we observed the accumulation and deformation of lipid droplets and a disrupted morphology of mitochondria, the key organelle where FAO takes place, in PLN R14del heart using transmission electron microscopy (TEM).Conclusion Using multi-omics approaches, we successfully obtained a unique list of chromatin regions and genes, including TF-coding genes, which played important roles in the metabolism-related signalling in PLN R14del hearts.Competing Interest StatementThe authors have declared no competing interest.