Cardiomyogenesis is controlled by the miR-99a/let-7c cluster and epigenetic modifications

Abstract

Understanding the molecular basis of cardiomyocyte development is critical for understanding the pathogenesis of pre- and post-natal cardiac disease. MicroRNAs (miRNAs) are post-transcriptional modulators of gene expression that play an important role in many developmental processes. Here, we show that the miR-99a/let-7c cluster, mapping on human chromosome 21, is involved in the control of cardiomyogenesis by altering epigenetic factors. By perturbing miRNA expression in mouse embryonic stem cells, we find that let-7c promotes cardiomyogenesis by upregulating genes involved in mesoderm specification (T/Bra and Nodal) and cardiac differentiation (Mesp1, Nkx2.5 and Tbx5). The action of let-7c is restricted to the early phase of mesoderm formation at the expense of endoderm and its late activation redirects cells toward other mesodermal derivatives. The Polycomb complex group protein Ezh2 is a direct target of let-7c, which promotes cardiac differentiation by modifying the H3K27me3 marks from the promoters of crucial cardiac transcription factors (Nkx2.5, Mef2c, Tbx5). In contrast, miR-99a represses cardiac differentiation via the nucleosome-remodeling factor Smarca5, attenuating the Nodal/Smad2 signaling. We demonstrated that the identified targets are underexpressed in human Down syndrome fetal heart specimens. By perturbing the expression levels of these miRNAs in embryonic stem cells, we were able to demonstrate that these miRNAs control lineage- and stage-specific transcription factors, working in concert with chromatin modifiers to direct cardiomyogenesis.

What people with Down Syndrome can teach us about cardiopulmonary disease

“…No published data are available evaluating maternal levels of Hsa21-encoded miRs with regard to CHD in Down syndrome. Let-7c controls lineage and stage-specific transcription factors that promote and direct cardiogenesis, while miR-99a has the opposite effects [142]. Thus, a balancing act of the levels of critical Hsa21-encoded miRs and/or proteins, rather than simply Hsa21 gene dosage, may ultimately govern the development of CAD.…”

An epigenetic perspective on the failing heart and pluripotent-derived-cardiomyocytes for cell replacement therapy

“…Both Bvht and Fendrr have been shown to bind PRC2 machinery, and by extension depletion of Fendrr and Bvht disrupts normal deposition/resolution of H3K4me3 or H3K27me3/H3K4me3, respectively, at a subset of cardiac developmental genes. In an analogous manner, miRNA let-7c was shown to promote pluripotent-CM differentiation through targeting of PRC2 member EZH2, and removal of repressive H3K27me3 at cardiac developmental genes (Coppola et al, 2014). As miR-99a is transcribed from the same miRNA cluster, it is intriguing that this miRNA, exerted opposite effects on CM differentiation.…”

A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1

“…In keeping with the known role of let-7 in differentiation, upregulation of let-7c accompanies maturation of the developing heart, and repression of let-7 permits cardiomyocyte de-differentiation and regeneration [27, 28]. Some let-7 species may participate in the response to hypertrophic signals [29], and miR-let-7 is dysregulated in the failing human heart [30].…”