Translational regulation medicated by lncRNA Miat in cardiac hypertrophy
Elevated protein synthesis is a fundamental mechanism contributing to a growing heart, during which both translation efficiency and capacity are enhanced (8-10). Translation efficiency focus on existing ribosomes in the cytosol, involving how signaling pathways regulate translation initiation, elongation, termination and ribosome recycling to affect translation in a cell(11-14). In the cardiomyocytes, mRNA of MHC loading to the polysomes(15), phosphorylation of ribosomal protein, S6, or of the peptide chain initiation factor, elF-4E by mTOR (16) are well-characterized mechanisms of translation efficiency regulation. While little of translation capacity, or ribosome biogenesis in the heart has been explored. � In the heart, ribosome biogenesis is vital in rapid growth conditions such as cardiac development, hypertrophy and pulmonary artery stenosis(9). The left ventricular weight increases 82% in 4 days following birth in the newborn pig(17) serves as a good example illustrating that regulation of translation efficiency only cannot meet the demand of elevated protein synthesis.
Biogenesis of ribosomes, the only and universal translation machinery in the cell, is a tremendous work. All three RNA polymerases, estimated 70% of mature ribosomes and more than 200 assembly factors are devoted in this tightly controlled process(7, 18, 19). It starts from rDNA transcription, the pre-ribosomal RNA 45S/47S is synthesized by Pol I, followed by ribosomal RNA processing in the nucleoli, carried out by ~150 exonucleases, processing factors and ribosomal subunit assembly factors. The rRNA stands as a scaffold to be decorated by ribosomal proteins, then exported into the cytosol as the 40S and 60S subunits. In the heart, regulation of this assembly chain is largely dark as only few studies examined the rDNA transcription level.
In the thesis, we identified a long non-coding RNA Miat is associated with cardiac hypertrophy from an unbiased approach and analyzed the transcriptional change in the pressure overload mouse model to discover that Miat regulates the ribosomal genes and ribosome assembly associated genes. To confirm its impact on translation, we found that Miat is required for increased protein synthesis in cardiomyocytes. More remarkably, lack of Miat showed protective effect to the heart in multiple stress-induced cardiac growth models. Mechanistically, we found that Miat binds to nucleolin (NCL) via conserved binding motifs, and such binding is vital for ribosome biogenesis. NCL is a protein required for rDNA transcription and functions as the early processor of 45S/47S rRNA (1, 20, 21), however, how NCL mediates 45S/47S rRNA processing in the nucleoli region remained unknown. We found that Miat-NCL binding is vital for rRNA processing, nucleoli formation and ribosome biogenesis in the cardiomyocytes. Therefore, our study provided one of the first detailed examples of how ribosome biogenesis is regulated in the heart and how alteration of translation capacity affects cardiac function in pathological growth.