Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

miR-1 as a Key Epigenetic Regulator in Early Differentiation of Cardiac Sinoatrial Region

Version 1 : Received: 11 March 2024 / Approved: 12 March 2024 / Online: 12 March 2024 (10:22:13 CET)

How to cite: García-Padilla, C.; Lozano-Velasco, E.; García-López, V.; Aránega, A.; Franco, D.; García-Martínez, V.; López-Sánchez, C. miR-1 as a Key Epigenetic Regulator in Early Differentiation of Cardiac Sinoatrial Region. Preprints 2024, 2024030693. https://doi.org/10.20944/preprints202403.0693.v1 García-Padilla, C.; Lozano-Velasco, E.; García-López, V.; Aránega, A.; Franco, D.; García-Martínez, V.; López-Sánchez, C. miR-1 as a Key Epigenetic Regulator in Early Differentiation of Cardiac Sinoatrial Region. Preprints 2024, 2024030693. https://doi.org/10.20944/preprints202403.0693.v1

Abstract

A large diversity of epigenetic factors, such as microRNAs and histones modifications, are known to be capable of regulating gene expression without altering DNA sequence itself. In particular, miR-1 is considered the first essential microRNA in cardiac development. In this study, miR-1 potential role in early cardiac chamber differentiation is analyzed through specific signaling pathways. For this, we performed in chick embryos functional experiments by means of miR-1 microinjections into the posterior cardiac precursors -of both primitive endocardial tubes- committed to sinoatrial region fates. Subsequently, embryos were subjected to whole mount in situ hybridization, immunohistochemistry and RT-qPCR analysis. As a relevant nov-elty, our results revealed that miR-1 increases Tbx5, Gata4 and AMHC1, while this microRNA diminishes Mef2c expression, during early differentiation of cardiac sinoatrial region. Further-more, we observed in this developmental context that miR-1 upregulates CRABPII and RARß, and downregulates CRABPI, which are three crucial factors in retinoic acid signaling pathway. Interestingly, we also noticed that miR-1 directly interacts with HDAC4 and Calmodulin, as well as with Erk2/MAPK1, which are three key factors actively involved in Mef2c regulation. Our study shows, for the first time, a key role of miR-1 as an epigenetic regulator in early differenti-ation of cardiac sinoatrial region through orchestrating opposite actions between retinoic acid and Mef2c, fundamental to properly assign cardiac cells to their respective heart chambers. A better understanding of those molecular mechanisms modulated by miR-1 will definitely help in fields applied to therapy and cardiac regeneration and repair.

Keywords

miR-1; epigenetic regulator; cardiac sinoatrial region; molecular mechanisms; HDAC4; Calmodulin; pErk2/MAPK1; Mef2c activity; retinoic acid signaling; cardiac development

Subject

Biology and Life Sciences, Cell and Developmental Biology

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