Identification of atrial-enriched lncRNA Walras linked to cardiomyocyte cytoarchitecture and atrial fibrillation
García-Padilla, Carlos (Universidad de Jaén)
Domínguez, Jorge N. (Universidad de Jaén)
Lodde, Valeria (University of Sassari. Department of Biomedical Sciences)
Munk, Rachel (Laboratory of Genetics and Genomics. National Institute on Aging IRP. National Institutes of Health)
Abdelmohsen, Kotb (Laboratory of Genetics and Genomics. National Institute on Aging IRP. National Institutes of Health)
Gorospe, Myriam (Laboratory of Genetics and Genomics. National Institute on Aging IRP. National Institutes of Health)
Jiménez-Sábado, Verónica (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Ginel, Antonino (Institut d'Investigació Biomèdica Sant Pau)
Hove-Madsen, Leif (Institut d'Investigació Biomèdica Sant Pau)
Aránega, Amelia (Universidad de Jaén)
Franco, Diego (Universidad de Jaén)

Data:	2022
Resum:	Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in humans. Genetic and genomic analyses have recently demonstrated that the homeobox transcription factor Pitx2 plays a fundamental role regulating expression of distinct growth factors, microRNAs and ion channels leading to morphological and molecular alterations that promote the onset of AF. Here we address the plausible contribution of long non-coding (lnc)RNAs within the Pitx2>Wnt>miRNA signaling pathway. In silico analyses of annotated lncRNAs in the vicinity of the Pitx2, Wnt8 and Wnt11 chromosomal loci identified five novel lncRNAs with differential expression during cardiac development. Importantly, three of them, Walaa, Walras, and Wallrd, are evolutionarily conserved in humans and displayed preferential atrial expression during embryogenesis. In addition, Walrad displayed moderate expression during embryogenesis but was more abundant in the right atrium. Walaa, Walras and Wallrd were distinctly regulated by Pitx2, Wnt8, and Wnt11, and Wallrd was severely elevated in conditional atrium-specific Pitx2-deficient mice. Furthermore, pro-arrhythmogenic and pro-hypertrophic substrate administration to primary cardiomyocyte cell cultures consistently modulate expression of these lncRNAs, supporting distinct modulatory roles of the AF cardiovascular risk factors in the regulation of these lncRNAs. Walras affinity pulldown assays revealed its association with distinct cytoplasmic and nuclear proteins previously involved in cardiac pathophysiology, while loss-of-function assays further support a pivotal role of this lncRNA in cytoskeletal organization. We propose that lncRNAs Walaa, Walras and Wallrd, distinctly regulated by Pitx2>Wnt>miRNA signaling and pro-arrhythmogenic and pro-hypertrophic factors, are implicated in atrial arrhythmogenesis, and Walras additionally in cardiomyocyte cytoarchitecture.
Ajuts:	Ministerio de Ciencia, Innovación y Universidades BFU2015-67131P
Nota:	Altres ajuts: Junta de Andalucía (CTS-446); NIA IRP; NIH.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Animals ; Atrial Fibrillation ; Cytoskeleton ; Heart Atria ; Humans ; Lncrna ; Mice ; Mice, Knockout ; Myocytes, Cardiac ; Post-transcriptional regulation ; RNA, Long Noncoding
Publicat a:	FASEB Journal, Vol. 36 Núm. 1 (january 2022) , p. e22051, ISSN 1530-6860

DOI: 10.1096/fj.202100844RR
PMID: 34861058

25 p, 2.6 MB

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