In a complex organ like the heart, consisting of multiple anatomical structures and various cell types, regulatory networks have been exquisitely designed to integrate numerous signaling pathways and transcription factors. This circuitry is further wired by interweaving multiple members within a given family of transcription factors, with each regulating specific cellular differentiation programs, so that they are activated at precise developmental time points. Perturbations in this finely tuned network can lead to major anatomical or functional abnormalities. Thus, delineating the gene programs regulated by each factor and the temporal relationships within a multi - gene family is essential to our understanding of the physiology and pathology of the heart. Myocyte enhancer factor - 2 (MEF2) is one of the key transcription factor families involved in cardiogenesis. MEF2 is a transcription factor encoded by four genes, mef2a, -b, -c, and -d in vertebrates which exhibit a high degree of sequence and functional similarity. While the transcriptional activities are largely interchangeable in vitro, targeted mutations in mice have revealed dramatically different phenotypes for the mef2 genes. A null mutation in the mef2c gene results in defective cardiac looping during embryonic development, whereas mef2a mutant mice exhibit post - natal cardiac abnormalities including myofibrillar disarray and mitochondrial deficiency. Mutant mef2d mice display alterations in stress - dependent cardiac remodeling. In contrast, mef2b mice are viable. These data suggest that each MEF2 factor has inherently different biological activities by controlling unique gene programs within the developing heart. Given the overt perinatal cardiac abnormalities in mef2a null mice we sought to molecularly characterize this phenotype by gene expression profiling. We identified two novel MEF2A target genes whose products localize to a specialized macromolecular complex known as the costamere. To further dissect the function of MEF2A in cardiac differentiation we want to molecularly dissect a broader subset of MEF2A - dependent genes linked to the costamere. We will also begin to identify unique gene expression signatures of MEF2A and MEF2C in muscle to gain a better understanding of the mechanisms by which two highly related transcription factors control different aspects of cellular differentiation. Finally, since nothing is known regarding the function of MEF2A in mature muscle we want to characterize the role of MEF2A in the adult heart.
The specific aims are: 1) to characterize a newly identified cohort of MEF2A - dependent genes linked to the costamere;2) to identify unique gene expression signatures of MEF2A and MEF2C, and 3) to investigate the role of MEF2A in the adult heart. The molecular dissection of MEF2 - dependent transcriptional pathways will be an important step in the development of genetic strategies to treat cardiovascular disease.

Public Health Relevance

This research will help us understand the genetic mechanisms by which regulatory genes and their pathways are precisely assembled in the formation and function of the heart. Our results will substantially contribute to our knowledge regarding the genetics of congenital cardiac disorders. Given the complex physiology of the heart our findings will also help launch new avenues in the development of pharmacological strategies for the treatment of heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073304-07
Application #
8103214
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2003-04-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
7
Fiscal Year
2011
Total Cost
$422,922
Indirect Cost
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Medrano, Jose L; Naya, Francisco J (2017) The transcription factor MEF2A fine-tunes gene expression in the atrial and ventricular chambers of the adult heart. J Biol Chem 292:20975-20988
Desjardins, Cody A; Naya, Francisco J (2017) Antagonistic regulation of cell-cycle and differentiation gene programs in neonatal cardiomyocytes by homologous MEF2 transcription factors. J Biol Chem 292:10613-10629
Desjardins, Cody A; Naya, Francisco J (2016) The Function of the MEF2 Family of Transcription Factors in Cardiac Development, Cardiogenomics, and Direct Reprogramming. J Cardiovasc Dev Dis 3:
Naya, Francisco J; Wang, Da-Zhi (2016) (MYO)SLIDing Our Way Into the Vascular Pool of Long Noncoding RNAs. Arterioscler Thromb Vasc Biol 36:2033-4
Clark, Amanda L; Maruyama, Sonomi; Sano, Soichi et al. (2016) miR-410 and miR-495 Are Dynamically Regulated in Diverse Cardiomyopathies and Their Inhibition Attenuates Pathological Hypertrophy. PLoS One 11:e0151515
Estrella, Nelsa L; Clark, Amanda L; Desjardins, Cody A et al. (2015) MEF2D deficiency in neonatal cardiomyocytes triggers cell cycle re-entry and programmed cell death in vitro. J Biol Chem 290:24367-80
Feng, Yi; Desjardins, Cody A; Cooper, Olivia et al. (2015) EGR1 Functions as a Potent Repressor of MEF2 Transcriptional Activity. PLoS One 10:e0127641
Clark, Amanda L; Naya, Francisco J (2015) MicroRNAs in the Myocyte Enhancer Factor 2 (MEF2)-regulated Gtl2-Dio3 Noncoding RNA Locus Promote Cardiomyocyte Proliferation by Targeting the Transcriptional Coactivator Cited2. J Biol Chem 290:23162-72
Estrella, Nelsa L; Desjardins, Cody A; Nocco, Sarah E et al. (2015) MEF2 transcription factors regulate distinct gene programs in mammalian skeletal muscle differentiation. J Biol Chem 290:1256-68
Estrella, Nelsa L; Naya, Francisco J (2014) Transcriptional networks regulating the costamere, sarcomere, and other cytoskeletal structures in striated muscle. Cell Mol Life Sci 71:1641-56

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