DNA makes RNA, RNA makes protein, and protein makes us. This central dogma of life provides a simple description how an organism develops: DNA serves as a blueprint of the genetic information, and proteins are its functional and structural manifestation, whereas RNA mediates this process as a plotted construction plan. However, the relation between the genetic code and its biological implementation is much more complicated than originally supposed. Exemplarily, regulation on the epigenetic levels and functional transcripts derived from the non–protein-coding dark matter of the genome step out of the classical flow of genetic information. This information, by large, changed our view of traditional biology and opened a new avenue of research and development of next-generation mechanism-orientated therapeutic concepts.
The function of the heart is profoundly influenced by the organization of the chromatin, an epigenetic landscape that modulates the activity of the cardiac transcription network. Reorganization of epigenetic marks involving aberrant gene expression is crucial for the dysfunction of the myocardium and leads to cardiac hypertrophy or progresses to heart failure. This process encompasses a complex interplay between various regulators that arise from the transcriptome and retain as functional transcripts, namely, noncoding RNAs including the subclass of long noncoding RNAs (lncRNAs). Despite a broad interest in lncRNAs, only a handful of transcripts have been well studied including regulators of cardiomyocyte differentiation like Braveheart and Fendrr or noncoding actors in cardiac remodeling like Myheart or Chast. We still know little about how lncRNAs act at the molecular level and their exact role in cardiac development and disease.
Chaer acts as an early epigenetic checkpoint in cardiac hypertrophic reprogramming
At the onset of cardiac hypertrophy, stress signaling induces a transient interaction between Chaer and EZH2 (Enhancer of zeste homolog 2) presumably sequestering this catalytic subunit of PRC2 (Polycomb Repressive Complex 2) from its target sites and from other competing lncRNAs like Hotair. The interaction is mediated by a bitetra-loop motif within the 5’ end of Chaer, hampers repressive PRC2-depedent H3 lysine 27 trimethylation and finally leads to an activation of the hypertrophic gene program.