Initiating Events in Direct Cardiomyocyte Reprogramming
Kimberly Sauls,
Todd M. Greco,
Li Wang,
Meng Zou,
Michelle Villasmil,
Li Qian,
Ileana M. Cristea,
Frank L. Conlon
Affiliations
Kimberly Sauls
University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, UNC-Chapel Hill, Chapel Hill, NC 27599 USA
Todd M. Greco
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Li Wang
University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Pathology and Laboratory Medicine, UNC-Chapel Hill, Chapel Hill, NC 27599, USA
Meng Zou
University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, UNC-Chapel Hill, Chapel Hill, NC 27599 USA
Michelle Villasmil
University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, UNC-Chapel Hill, Chapel Hill, NC 27599 USA; Lineberger Comprehensive Cancer Center, UNC-Chapel Hill, Chapel Hill, NC 27599, USA
Li Qian
University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Pathology and Laboratory Medicine, UNC-Chapel Hill, Chapel Hill, NC 27599, USA
Ileana M. Cristea
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Frank L. Conlon
University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, UNC-Chapel Hill, Chapel Hill, NC 27599 USA; Lineberger Comprehensive Cancer Center, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Integrative Program for Biological and Genome Sciences, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding author
Summary: Direct reprogramming of fibroblasts into cardiomyocyte-like cells (iCM) holds great potential for heart regeneration and disease modeling and may lead to future therapeutic applications. Currently, application of this technology is limited by our lack of understanding of the molecular mechanisms that drive direct iCM reprogramming. Using a quantitative mass spectrometry-based proteomic approach, we identified the temporal global changes in protein abundance that occur during initial phases of iCM reprogramming. Collectively, our results show systematic and temporally distinct alterations in levels of specific functional classes of proteins during the initiating steps of reprogramming including extracellular matrix proteins, translation factors, and chromatin-binding proteins. We have constructed protein relational networks associated with the initial transition of a fibroblast into an iCM. These findings demonstrate the presence of an orchestrated series of temporal steps associated with dynamic changes in protein abundance in a defined group of protein pathways during the initiating events of direct reprogramming.
