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Transcriptomic Analysis of Human Lung Development

¹ Children's Hospital Informatics Program, Harvard–MIT Division of Health Sciences and Technology, Boston, Massachusetts; ² Division of Neonatology and Center for Pediatric Biomedical Research, University of Rochester, Rochester, New York; ³ Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts; and ⁴ Division of Clinical Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri

Correspondence and requests for reprints should be addressed to Thomas J. Mariani, Ph.D., Dept. of Pediatrics, University of Rochester, 601 Elmwood Avenue, Box 703, Rochester, NY 14642. E-mail: tom_mariani{at}urmc.rochester.edu; or Scott T. Weiss, M.D., Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115.

Rationale: Current understanding of the molecular regulation of lung development is limited and derives mostly from animal studies.

Objectives: To define global patterns of gene expression during human lung development.

Methods: Genome-wide expression profiling was used to measure the developing lung transcriptome in RNA samples derived from 38 normal human lung tissues at 53 to 154 days post conception. Principal component analysis was used to characterize global expression variation and to identify genes and bioontologic attributes contributing to these variations. Individual gene expression patterns were verified by quantitative reverse transcriptase–polymerase chain reaction analysis.

Measurements and Main Results: Gene expression analysis identified attributes not previously associated with lung development, such as chemokine-immunologic processes. Lung characteristics attributes (e.g., surfactant function) were observed at an earlier-than-anticipated age. We defined a 3,223 gene developing lung characteristic subtranscriptome capable of describing a majority of the process. In gene expression space, the samples formed a time-contiguous trajectory with transition points correlating with histological stages and suggesting the existence of novel molecular substages. Induction of surfactant gene expression characterized a pseudoglandular "molecular phase" transition. Individual gene expression patterns were independently validated. We predicted the age of independent human lung transcriptome profiles with a median absolute error of 5 days, supporting the validity of the data and modeling approach.

Conclusions: This study extends our knowledge of key gene expression patterns and bioontologic attributes underlying early human lung developmental processes. The data also suggest the existence of molecular phases of lung development.

Key Words: microarrays • surfactant • principal component analysis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Knowledge of lung development in humans has been largely derived from gross anatomical staging with limited molecular studies. High throughput technologies have enabled comprehensive studies of organogenesis in animal models, but corresponding studies in humans are lacking. What This Study Adds to the Field We provide a unique data set significantly expanding current knowledge of gene expression patterns in the developing human lung in particular and in human organogenesis in general. From these data, we have identified essential attributes characterizing the biology of the lung, which should facilitate our understanding of lung disease pathogenesis.