Investigating the Role of MBNL1 in Maintaining Cardiomyocyte Terminal Differentiation.

PROJECT ABSTRACT/SUMMARY.
Cardiomyocyte cell state is dramatically altered during postnatal development. During this period,
cardiomyocytes terminally differentiate, fundamentally changing their energetics, functional machinery, and
mechanism of cell growth. Although we have a good understanding of the factors controlling embryonic heart
development, we still have a poor understanding of the mechanisms that establish cardiomyocyte terminal
differentiation during postnatal development and maintain this cell state in the adult. Critically, cardiomyocyte
terminal differentiation is integrally linked to cardiac remodeling and regeneration. While a terminally
differentiated transcriptome is necessary for cardiomyocytes to accommodate adult circulatory demands, this
transcriptional program also suppresses cardiomyocyte proliferation, underlying the inability of the mammalian
heart to meaningfully regenerate after injury. Indeed, in model systems of cardiac regeneration, cardiomyocytes
must first de-differentiate and return to a fetal-like transcriptomic state in order to proliferate. Few studies examine
the factors responsible for maintaining cardiomyocyte terminal differentiation, but it stands to reason that targeted
disruption of cardiomyocyte terminal differentiation could unmask latent pro-proliferative pathways in the adult
heart and promote endogenous cardiac regeneration.
In this study, we will examine the role of the RNA-binding protein Muscleblind-like protein 1 (MBNL1) in
controlling cardiomyocyte terminal differentiation and cardiac regeneration. Although MBNL1 expression
increases during cardiomyocyte terminal differentiation and MBNL1 is known to promote fetal-to-adult isoform
switching of a number of developmentally regulated genes, it has never been examined directly for controlling
cardiomyocyte terminal differentiation or integrated into regulatory mechanisms surrounding cardiac plasticity.
Specifically, this proposal will use a variety of in vivo and in vitro genetic approaches to address the following
aims: (1) to determine the role of MBNL1 in maintaining cardiomyocyte terminal differentiation in the adult
mammalian heart and (2) to determine the role of MBNL1 in controlling cardiac regenerative potential. Insight
gleaned from these aims will characterize MBNL1-dependent post-transcriptional regulatory mechanisms
governing cardiomyocyte terminal differentiation and will determine if MBNL1 could be used as a novel
therapeutic target to promote endogenous cardiac regeneration.

Grant Number: 5F30HL163926-04
NIH Institute/Center: NIH
Principal Investigator: Logan Bailey