Early Atf4 activity drives airway club and goblet cell differentiation

Author:

Barrera-Lopez Juan F1,Cumplido-Laso Guadalupe1,Olivera-Gomez Marcos1ORCID,Garrido-Jimenez Sergio1,Diaz-Chamorro Selene1,Mateos-Quiros Clara M1,Benitez Dixan A1,Centeno Francisco1ORCID,Mulero-Navarro Sonia1ORCID,Roman Angel C1,Carvajal-Gonzalez Jose M1ORCID

Affiliation:

1. Departamento de Bioquímica, Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura

Abstract

Activating transcription factor 4 (Atf4), which is modulated by the protein kinase RNA-like ER kinase (PERK), is a stress-induced transcription factor responsible for controlling the expression of a wide range of adaptive genes, enabling cells to withstand stressful conditions. However, the impact of the Atf4 signaling pathway on airway regeneration remains poorly understood. In this study, we used mouse airway epithelial cell culture models to investigate the role of PERK/Atf4 in respiratory tract differentiation. Through pharmacological inhibition and silencing of ATF4, we uncovered the crucial involvement of PERK/Atf4 in the differentiation of basal stem cells, leading to a reduction in the number of secretory cells. ChIP-seq analysis revealed direct binding of ATF4 to regulatory elements of genes associated with osteoblast differentiation and secretory cell function. Our findings provide valuable insights into the role of ATF4 in airway epithelial differentiation and its potential involvement in innate immune responses and cellular adaptation to stress.

Funder

Ministry of Economy

Junta de Extremadura

Universidad de Extremadura

Publisher

Life Science Alliance, LLC

Subject

Health, Toxicology and Mutagenesis,Plant Science,Biochemistry, Genetics and Molecular Biology (miscellaneous),Ecology

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