Changes in gene methylation patterns in neonatal murine hearts: Implications for the regenerative potential

Abstract

BackgroundThe neonatal murine heart is able to regenerate after severe injury; this capacity however, quickly diminishes and it is lost within the first week of life. DNA methylation is an epigenetic mechanism which plays a crucial role in development and gene expression regulation. Under investigation here are the changes in DNA methylation and gene expression patterns which accompany the loss of regenerative potential.ResultsThe MeDIP-chip (methylated DNA immunoprecipitation microarray) approach was used in order to compare global DNA methylation profiles in whole murine hearts at day 1, 7, 14 and 56 complemented with microarray transcriptome profiling. We found that the methylome transition from day 1 to day 7 is characterized by the excess of genomic regions which gain over those that lose DNA methylation. A number of these changes were retained until adulthood. The promoter genomic regions exhibiting increased DNA methylation at day 7 as compared to day 1 are significantly enriched in the genes critical for heart maturation and muscle development. Also, the promoter genomic regions showing an increase in DNA methylation at day 7 relative to day 1 are significantly enriched with a number of transcription factors binding motifs including those of Mfsd6l, Mef2c, Meis3, Tead4, and Runx1.ConclusionsThe results indicate that the extensive alterations in DNA methylation patterns along the development of neonatal murine hearts are likely to contribute to the decline of regenerative capabilities observed shortly after birth. This conclusion is supported by the evidence that an increase in DNA methylation in the neonatal murine heart from day 1 to day 7 occurs in the promoter regions of genes playing important roles in cardiovascular system development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2545-1) contains supplementary material, which is available to authorized users.

RUNX1: an emerging therapeutic target for cardiovascular disease

“… 38 Although the reasons for this are unexplored, it is interesting to note that genes with RUNX1-binding sites within their promoter region are overrepresented in the collection of genes that become methylated during the first week of life. 39 Promoter methylation is an epigenetic modification which usually leads to gene silencing by blocking the access of transcriptional machinery. 40 In this setting, increased gene methylation may be important in the maturation process by switching off genes necessary for heart development to support transition to a more adult phenotype.…”

Effects of ionizing radiation on the heart

“…Recently, alterations in DNA methylation have been described in the heart in response to protons and iron ions [113;114]. The role of DNA methylation in cardiac function and disease has only recently started to emerge [115–117]. For instance, changes in gene-specific methylation were reported in dilated cardiomyopathy, arrhythmia and in heart failure [118–122].…”

Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

“…It has been shown that Runx1 is important in skeletal muscle stem cell (SC) proliferation and its levels can affect the proliferative timing and thus the regenerative capacity of skeletal muscle cells (23). In the heart, Runx1 is expressed in neonatal mouse cardiomyocytes and is upregulated in zebrafish, adult mouse, rat and human cardiomyocytes after injury (24)(25)(26)(27)(28). Conditional Runx1 deficiency in mouse cardiomyocytes has been demonstrated to protect the mouse against the negative consequences of cardiac remodelling after myocardial infarction (29).…”