A single-cell regulatory map of postnatal lung alveologenesis in humans and mice

• Published in: Cell genomics Vol. 2; no. 3; p. 100108
• Main Authors: Duong, Thu Elizabeth, Wu, Yan, Sos, Brandon Chin, Dong, Weixiu, Limaye, Siddharth, Rivier, Lauraine H., Myers, Greg, Hagood, James S., Zhang, Kun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.03.2022; Elsevier
• Subjects: alveolus; chromatin accessibility; human cell atlas; lung development; mouse cell atlas; transcriptional regulation; human cell atlas; mouse cell atlas; transcriptional regulation; lung development; alveolus; chromatin accessibility
• ISSN: 2666-979X; 2666-979X
• DOI: 10.1016/j.xgen.2022.100108

Ex-utero regulation of the lungs’ responses to breathing air and continued alveolar development shape adult respiratory health. Applying single-cell transposome hypersensitive site sequencing (scTHS-seq) to over 80,000 cells, we assembled the first regulatory atlas of postnatal human and mouse lung alveolar development. We defined regulatory modules and elucidated new mechanistic insights directing alveolar septation, including alveolar type 1 and myofibroblast cell signaling and differentiation, and a unique human matrix fibroblast population. Incorporating GWAS, we mapped lung function causal variants to myofibroblasts and identified a pathogenic regulatory unit linked to lineage marker FGF18, demonstrating the utility of chromatin accessibility data to uncover disease mechanism targets. Our regulatory map and analysis model provide valuable new resources to investigate age-dependent and species-specific control of critical developmental processes. Furthermore, these resources complement existing atlas efforts to advance our understanding of lung health and disease across the human lifespan. [Display omitted] Chromatin accessibility map of human and mouse postnatal alveolar developmentConstruction of regulatory modules directing alveolar cell differentiationTemporal and interspecies gene regulation of mechanical stretch signalingDisease risk variants mapped to regulatory units in developmental cell types Duong et al. produce single-cell chromatin accessibility profiles from human and mouse lungs during critical alveolar development stages after birth. They present a computational template to characterize developmental cell types, construct regulatory modules to propose cell lineage-specific transcription factors directing expression of marker genes, and identify regulatory units critical to pathogenesis.