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Joel Perez-Perri Lab
RNA Regulation and Aging
Joel Perez-Perri Lab
RNA Regulation and Aging
Aging is characterized by a progressive decline in cellular homeostasis and stands as the single most significant risk factor for many prevalent human diseases. At the heart of cellular homeostasis is the cell’s ability to control gene expression, which entails the production of the RNAs and proteins required for proper cellular function. Crucial steps in gene expression regulation are elicited at the RNA level by RNA-binding proteins (RBPs) and non-coding RNAs. There is mounting evidence suggesting that many of these processes become compromised in our tissues as we get old. However, the origin, extent and functional implications of these alterations remain poorly understood. Our primary objective is to decipher how RBP malfunction and disruptions in RNA regulatory processes contribute to the aging process, and to utilize this knowledge to develop novel therapies aimed at promoting healthspan.
Our work bridges RNA biology and aging research, utilizing cutting-edge systems and molecular technologies to investigate the underlying mechanisms of age-related tissue decline. We are currently focusing on two main research areas.
Understanding proteome-transcriptome decoupling in aging
RNA profiling of tissues has revealed age-associated transcriptional changes, which are at least partly attributed to the loss of epigenetic information. Far from being merely a consequence of aging, some of these changes in RNA biogenesis drive the aging process. However, they cannot fully explain the impact of aging on tissue proteomes, as a significant fraction of age-associated changes in protein levels have no corresponding changes in their mRNAs. Indeed, there is a progressive decoupling of RNA and protein expression during aging that has been observed in various organs and across multiple species. While the molecular origins of these alterations remain elusive, they suggest the involvement of posttranscriptional regulators like RBPs. We are working to identify RBPs that contribute to the progressive decoupling of the transcriptome and proteome with age and to assess their impact on the decline of tissue function.
Role of splicing deterioration in senescence
Aging entails the accumulation of senescent cells in multiple organs. These cells compromise tissue function and secrete molecules that induce inflammation, further disrupting tissue and systemic homeostasis. Cellular senescence is associated with a widespread downregulation of splicing machinery components, leading to splicing alterations. Furthermore, a defective splicing machinery is sufficient to drive senescence. We investigate how splicing deterioration induces cellular senescence and whether interventions aimed at restoring splicing fidelity can counteract the senescent phenotype.
Perez-Perri JI, Ferring-Appel D, Huppertz I, Schwarzl T, Sahadevan S, Stein F, Rettel M, Galy B, Hentze MW (2023) The RNA-binding protein landscapes differ between mammalian organs and cultured cells. Nature Commun. 14(1):2074. DOI: 10.1038/s41467-023-37494-w.
Huppertz I, Perez-Perri JI, Mantas P, Sekaran T, Schwarzl T, Dimitrova-Paternoga L, Hennig A, Neveau PA, Hentze MW (2022) RNA regulates glycolysis and embryonic stem cell differentiation via Enolase 1. Mol Cell. DOI: 10.1016/j.molcel.2022.05.019.
Perez-Perri JI, Noerenberg M, Kamel W, Lenz C, Mohammed S, Hentze MW, Castello A (2021) Global analysis of RNA-binding protein dynamics by comparative and enhanced RNA interactome capture. Nature Protoc. 16(1):27-60. DOI: 10.1038/s41596-020-00404-1.
Backlund M, Stein F, Rettel M, Schwarzl T, Perez-Perri JI, Brosig A, Zhou Y, Neu-Yilik G, Hentze MW, Kulozik AE (2020) Plasticity of nuclear and cytoplasmic stress responses of RNA-binding proteins. Nucleic Acids Res. 48(9):4725-4740.
Perez-Perri JI, Rogell B, Schwarzl T, Stein F, Zhou Y, Rettel M, Brosig A, Hentze MW (2018) Discovery of RNA-binding proteins and characterization of their dynamic responses by enhanced RNA interactome capture. Nature Commun. 9(1):4408.
Melani M, Valko A, Romero NM, Aguilera MO, Acevedo JM, Bhujabal Z, Perez-Perri J, de la Riva-Carrasco RV, Katz MJ, Sorianello E, D’Alessio C, Juhász G, Johansen T, Colombo MI, Wappner P (2017) Zonda is a novel early component of the autophagy pathway in Drosophila. Mol Biol Cell. 28(22):3070-3081.
Perez-Perri JI, Dengler VL, Audetat KA, Pandey A, Bonner EA, Urh M, Mendez J, Daniels DL, Wappner P, Galbraith MD, Espinosa JM (2016) The TIP60 Complex Is a Conserved Coactivator of HIF1A. Cell Rep. 16(1):37-47.
Perez-Perri JI, Acevedo JM, Wappner P (2011) Epigenetics: New Questions on the Response to Hypoxia. Int J Mol Sci. 12(7).
Dekanty A, Romero NM, Bertolin AP, Thomas MG, Leishman CC, Perez-Perri JI, Bocaccio GL, Wappner P (2010) Drosophila Genome-Wide RNAi Screen Identifies Multiple Regulators of HIF–Dependent Transcription in Hypoxia. PLoS Genet. 6(6).
2012: Cold Spring Harbor Laboratory Scholarship, USA
2010-2012: Cardini award (outstanding doctoral student), Fundación Instituto Leloir, Argentina
2010: Best poster award at the 5th International Meeting of the Latin American Society for Developmental Biology, Chile
2010: Keystone Symposia Scholarship, USA
Team
