Micropeptide control of calcium signaling in the cardiovascular system
We recently discovered a 46 amino acid micropeptide, myoregulin (MLN), concealed within a muscle-specific RNA believed to be non-coding. MLN shares structural and functional similarity with phospholamban (PLN) and sarcolipin (SLN), two cardiac micropeptides that inhibit SERCA, the membrane pump that controls muscle relaxation by regulating calcium uptake into the sarcoplasmic reticulum (SR). MLN similarly interacts with SERCA and impedes calcium uptake into the SR (Figure 1A and B). Since PLN and SLN are expressed predominantly in the adult heart, MLN functions as the dominant regulator of SERCA in adult fast-type skeletal muscles. Consistent with this finding, genetic deletion of MLN in mice resulted in enhanced calcium handling and improved exercise performance.
In addition to the essential role that SERCA plays in regulating striated muscle contractility, SERCA plays an important role in regulating calcium signaling across diverse cell types, which do not express MLN, PLN or SLN. We have subsequently identified two additional transmembrane micropeptides, that we named endoregulin (ELN) and another-regulin (ALN), that overlap with the expression of SERCA isoforms in non-muscle cell types (Figure 1B). ELN overlaps with SERCA3 in endothelial and epithelial cells of vascular and visceral organs and ALN overlaps with the broadly expressed isoform SERCA2b. These findings reveal a general mechanism for the control of calcium handling across diverse cell types by a family of structurally and functionally related micropeptides. Considering the importance of intracellular calcium dynamics for many cellular processes (muscle relaxation, cardiac hypertrophy, smooth muscle relaxation, platelet cell activation, etc.), projects in my lab will focus on the role of these micropeptides in regulating the development and function of the cardiovascular system.
Role of lncRNAs in cardiovascular development, function and disease
Many RNA transcripts identified by deep sequencing are bona fide lncRNAs and do not appear to generate stable proteins. While challenging to study, recent advances in RNA probing techniques have allowed us to elucidate their function in vitro and in vivo. Interestingly, we’ve found that many lncRNA transcripts are located near essential cardiac-specific transcription factors and are required for normal development and survival (Figure 2). Using novel knockout approaches that prematurely stop the transcription of these RNAs, we have been able to assess their roles in vivo. Current projects in our lab include the study of cardiac-enriched lncRNAs and their role in heart development, function and disease.