Abstract
The heart is a highly specialized organ with essential function for the organism throughout life. The significance of DNA methylation in shaping the phenotype of the heart remains only partially known. Here we generate and analyse DNA methylomes from highly purified cardiomyocytes of neonatal, adult healthy and adult failing hearts. We identify large genomic regions that are differentially methylated during cardiomyocyte development and maturation. Demethylation of cardiomyocyte gene bodies correlates strongly with increased gene expression. Silencing of demethylated genes is characterized by the polycomb mark H3K27me3 or by DNA methylation. De novo methylation by DNA methyltransferases 3A/B causes repression of fetal cardiac genes, including essential components of the cardiac sarcomere. Failing cardiomyocytes partially resemble neonatal methylation patterns. This study establishes DNA methylation as a highly dynamic process during postnatal growth of cardiomyocytes and their adaptation to pathological stress in a process tightly linked to gene regulation and activity.
Highlights
The heart is a highly specialized organ with essential function for the organism throughout life
An antibody against pericentriolar material 1 (PCM1)[20] was used to isolate cardiomyocyte nuclei using flow cytometry (fluorescenceactivated cell sorting (FACS)) or magnetic-assisted nuclei sorting with very high purity (497%; Fig. 1b; Supplementary Fig. 1a–c)
The overlap of mCherry and PCM1-positive nuclei was 495% confirming that PCM1 stains cardiomyocyte nuclei (Supplementary Fig. 1g)
Summary
The heart is a highly specialized organ with essential function for the organism throughout life. This study establishes DNA methylation as a highly dynamic process during postnatal growth of cardiomyocytes and their adaptation to pathological stress in a process tightly linked to gene regulation and activity. DNA methylation is a stable hallmark of cell type identity and is essential for mammalian development[11,12]. It occurs mainly in palindromic CpG dinucleotides. We show that DNA methylation is highly dynamic during cardiomyocyte development, postnatal maturation and disease. Postnatal DNA demethylation correlates with active histone marks and increased gene expression. Dynamic DNA methylation is important for the perinatal switch in sarcomere protein isoforms and postnatal cardiomyocyte maturation and adaptation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
