PBX/Knotted 1 homeobox-2 (PKNOX2) is a novel regulator of myocardial fibrosis
Chen, Liang (Fuwai Hospital (Xina))
Li, Haotong (Fuwai Hospital (Xina))
Liu, Xiaorui (Fuwai Hospital (Xina))
Zhang, Ningning (Fuwai Hospital (Xina))
Wang, Kui (Nankai University (Xina))
Shi, Anteng (Fuwai Hospital (Xina))
Gao, Hang (Fuwai Hospital (Xina))
Akdis, Deniz (University Hospital Zurich (Suïssa))
Saguner, Ardan M. (University Hospital Zurich (Suïssa))
Xu, Xinjie (Fuwai Hospital (Xina))
Osto, Elena (University Hospital Zurich (Suïssa))
Van de Veen, Willem (University of Zurich)
Li, Guangyu (Fuwai Hospital (Xina))
Bayés-Genís, Antoni (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Duru, Firat (University Hospital Zurich (Suïssa))
Song, Jiangping (Fuwai Hospital (Xina))
Li, Xiangjie (Fuwai Hospital (Xina))
Hu, Shengshou (Fuwai Hospital (Xina))

Fecha:	2024
Resumen:	Much effort has been made to uncover the cellular heterogeneities of human hearts by single-nucleus RNA sequencing. However, the cardiac transcriptional regulation networks have not been systematically described because of the limitations in detecting transcription factors. In this study, we optimized a pipeline for isolating nuclei and conducting single-nucleus RNA sequencing targeted to detect a higher number of cell signal genes and an optimal number of transcription factors. With this unbiased protocol, we characterized the cellular composition of healthy human hearts and investigated the transcriptional regulation networks involved in determining the cellular identities and functions of the main cardiac cell subtypes. Particularly in fibroblasts, a novel regulator, PKNOX2, was identified as being associated with physiological fibroblast activation in healthy hearts. To validate the roles of these transcription factors in maintaining homeostasis, we used single-nucleus RNA-sequencing analysis of transplanted failing hearts focusing on fibroblast remodelling. The trajectory analysis suggested that PKNOX2 was abnormally decreased from fibroblast activation to pathological myofibroblast formation. Both gain- and loss-of-function in vitro experiments demonstrated the inhibitory role of PKNOX2 in pathological fibrosis remodelling. Moreover, fibroblast-specific overexpression and knockout of PKNOX2 in a heart failure mouse model induced by transverse aortic constriction surgery significantly improved and aggravated myocardial fibrosis, respectively. In summary, this study established a high-quality pipeline for single-nucleus RNA-sequencing analysis of heart muscle. With this optimized protocol, we described the transcriptional regulation networks of the main cardiac cell subtypes and identified PKNOX2 as a novel regulator in suppressing fibrosis and a potential therapeutic target for future translational studies.
Derechos:	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, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Animals ; Fibrosis ; Genes, Homeobox ; Heart ; Humans ; Mice ; RNA ; Transcription Factors
Publicado en:	Signal Transduction and Targeted Therapy, Vol. 9 Núm. 1 (december 2024) , p. 94, ISSN 2059-3635

DOI: 10.1038/s41392-024-01804-5
PMID: 38644381

19 p, 11.3 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Artículos > Artículos de investigación
Artículos > Artículos publicados