Transcriptional Programs and Regeneration Enhancers Underlying Heart Regeneration

Abstract

The heart plays the vital role of propelling blood to the entire body, which is essential to life. While maintaining heart function is critical, adult mammalian hearts poorly regenerate damaged cardiac tissue upon injury and form scar tissue instead. Unlike adult mammals, adult zebrafish can regenerate injured hearts with no sign of scarring, making zebrafish an ideal model system with which to study the molecular mechanisms underlying heart regeneration. Investigation of heart regeneration in zebrafish together with mice has revealed multiple cardiac regeneration genes that are induced by injury to facilitate heart regeneration. Altered expression of these regeneration genes in adult mammals is one of the main causes of heart regeneration failure. Previous studies have focused on the roles of these regeneration genes, yet the regulatory mechanisms by which the expression of cardiac regeneration genes is precisely controlled are largely unknown. In this review, we will discuss the importance of differential gene expression for heart regeneration, the recent discovery of cardiac injury or regeneration enhancers, and their impact on heart regeneration.

Keywords: development; enhancer; gene regulation; heart; regeneration; transcription; zebrafish.

Figure 1

Differential gene expression affects regenerative ability. (A) Fstl1 expression in the mouse heart is altered upon injury. In uninjured hearts, the epicardium produces Fstl1, which has the potential to promote cardiomyocyte (CM) proliferation. However, in injured hearts, Fstl1 is mainly produced by the myocardium rather than the epicardium. Fstl1 derived from the myocardium appears to be unable to promote CM proliferation due to glycosylation. (B) The level of Erbb2, a receptor of Nrg1, declines after birth, resulting in poor regenerative capacity in the mouse heart. (C) In zebrafish, Erbb2 expression is maintained throughout life, and a sustained Erbb2 level contributes to retaining cardiac regenerative capacity in the adult stage. (D) The expression level of the miRNA-15 family and miRNA-128 increases after birth in mice to inhibit heart regeneration. However, it is unclear whether expression of these miRNA is maintained upon injury. (E) The expression level of miRNA-101a is dynamic during heart regeneration in adult zebrafish. Depletion of miRNA-101a in the early regenerative stage promotes CM proliferation, while the presence of miRNA-101a in the late regenerative stage contributes to scar tissue removal. The ability to precisely modulate miRNA expression during heart regeneration enables zebrafish to retain remarkable regenerative capacity. In (B,D): E/F, embryonic/fetal period; B, birth; P, postnatal period.

Figure 2

Epicardial enhancers are activated by development cues and cardiac injury. Several evolutionarily conserved regions near epicardial factors are activated during development and upon cardiac injury to drive gene expression in epicardium. C/EBP and the SWI/SNF complex mediate epicardial enhancer activation.

Figure 3

Cardiac regeneration enhancer elements. (A) Cardiomyocyte (CM)-specific enhancers in zebrafish. CM-specific histone H3.3 profiling of uninjured and regenerating zebrafish hearts captures regulatory elements preferential for heart development and regeneration. (B) ChIP-seq analysis with active enhancer markers, such as H3K27ac, identifies lepb-linked regeneration enhancer (LEN), which can direct regeneration-specific expression in hearts and fins of zebrafish. (C) LEN consists of tissue-specific regeneration modules, each of which mediates gene transcription in their target tissues.