The Accornero Lab at Brown University studies RNA Biology in the context of cardiac and skeletal muscle disease.
Welcome to the Accornero Lab!
Publications
Check out some of our recent work below
AIMP3 maintains cardiac homeostasis by regulating the editing activity of methionyl-tRNA synthetase
Nature Cardiovascular Research
Anindhya S. Das, Charles P. Rabolli, Colton R. Martens, Han-Kai Jiang, Yingshen Zhang, Aubree A. Zimmer, Kevin Lin, Kedryn K. Baskin, Juan D. Alfonzo & Federica Accornero
Abstract
In mammals, nine aminoacyl tRNA synthetases (ARSs) and three auxiliary proteins (ARS-interacting multifunctional proteins 1–3 (AIMP1–3)) form the multisynthetase complex (MSC), a molecular hub that provides a subset of aminoacylated tRNAs to the ribosome and partakes in translation-independent signaling. Knowledge of the role of AIMPs in organ physiology is currently limited. AIMP3 (also known as EEF1E1) was proposed to anchor methionyl tRNA synthetase (MetRS) in the complex and regulate protein synthesis through translation initiation and elongation. Here we show that a cardiomyocyte-specific conditional knockout of AIMP3 in mice leads to lethal cardiomyopathy. MetRS localization, aminoacylation efficiency and global protein synthesis were unaffected in our model, suggesting an alternative mechanism for the pathology. We found that AIMP3 is essential for homocysteine editing by MetRS, a reaction that is necessary for the maintenance of translation fidelity. Homocysteine accumulation induced reactive oxygen species production, protein aggregation, mitochondrial dysfunction, autophagy and ultimately cell death.
YTHDF2 in cardiomyocytes of adult mice drove cardiac dysfunction. By proteomics, we found myocardial zonula adherens protein (MYZAP) within the top up-regulated proteins in knockout cardiomyocytes. We further demonstrated that YTHDF2 binds m6A-modified Myzap messenger RNA and controls its stability. Cardiac overexpression of MYZAP has been associated with cardiomyopathy. Thus, our findings provide an important new mechanism for the YTHDF2-dependent regulation of this target and therein its novel role in the maintenance of cardiac homeostasis.
The m6A-binding protein YTHDF3 modulates the cardiac response to stress
RNA
Charles P. Rabolli, Anindhya S. Das, Volha A. Golubeva, Jop H. van Berlo and Federica Accornero
Abstract
Transcriptional regulation of gene expression has long been studied; however, only recently has the impact of chemical mRNA modification on protein synthesis emerged. Among posttranscriptional modifications, methylation of the N6-adenosine site of mRNA (m6A) is very prevalent in eukaryotes and plays a critical role in the heart. To date, the mechanism through which m6A controls cardiac function remains elusive. The fate of m6A-modified mRNAs is regulated by members of the YTH domain family (YTHDF), such as YTHDF3. Here we report that mice with a cardiomyocyte-specific deletion of YTHDF3 have attenuated pathological remodeling following pressure overload injury. Mechanistically, we found that YTHDF3 regulates global stress-induced protein synthesis, and that this protein controls cardiomyocyte size. Altogether, this study uncovered a potential cardioprotective role for YTHDF3 inhibition and improves our understanding on the mechanism through which m6A impacts cardiac function.
YTHDF1 is pivotal for maintenance of cardiac homeostasis
Journal of Molecular and Cellular Cardiology
Volha A. Golubeva, Anindhya Sundar Das, Charles P. Rabolli, Lisa E. Dorn, Jop H. van Berlo, Federica Accornero
Abstract
The YTH-domain family (YTHDF) of RNA binding proteins can control gene expression at the post-transcriptional level by regulating mRNAs with N6-methyladenosine (m6A) modifications. Despite the established importance of m6A in the heart, the cardiac role of specific m6A-binding proteins remains unclear. Here, we characterized the function of YTHDF1 in cardiomyocytes using a newly generated cardiac-restricted mouse model. Deletion of YTHDF1 in adult cardiomyocytes led to hypertrophy, fibrosis, and dysfunction. Using mass spectrometry, we identified the necessity of YTHDF1 for the expression of cardiomyocyte membrane raft proteins. Specifically, YTHDF1 bound to m6A-modified Caveolin 1 (Cav1) mRNA and favored its translation. We further demonstrated that YTHDF1 regulates downstream ERK signaling. Altogether, our findings highlight a novel role for YTHDF1 as a post-transcriptional regulator of caveolar proteins which is necessary for the maintenance of cardiac function.